Glucopyranosyl derivative and use thereof

ABSTRACT

A glucopyranosyl derivative is used as an inhibitor of sodium-dependent glucose transporters (SGLTs), particularly being used as an inhibitor of sodium-dependent glucose transporter-1 (SGLT1), and a pharmaceutically acceptable salt or stereoisomer thereof, further relating to a pharmaceutical composition containing the derivative. The compound and a pharmaceutical composition is used thereof in the preparation of a drug for treating diabetes and diabetes-related diseases.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the priority and benefits of Chinese PatentApplication No. 201810093154.8, filed with the State IntellectualProperty Office of China on Jan. 31, 2018, which is incorporated hereinby reference in its entirety.

FIELD OF THE INVENTION

The present invention belongs to the field of medicine, and specificallyrelates to a glucopyranosyl derivative that is used as an inhibitor ofsodium-dependent glucose transporter (SGLTs), particularly being used asan inhibitor of sodium-dependent glucose transporter 1 (SGLT1), theirpreparation methods, pharmaceutical compositions containing thederivatives, and uses of the derivatives and compositions thereof. Morespecifically, it relates to a compound having Formula (I), or apharmaceutically acceptable salt, or a stereoisomer thereof, or apharmaceutical composition containing the compound, and the uses of thecompound and the pharmaceutical composition thereof in the manufactureof a medicament for the treatment of diabetes and diabetes-relateddiseases.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a common chronic disease, characterized byhyperglycemia. The onset of diabetes associates with insulin resistancein peripheral tissue, reduction of insulin in vivo and increase ofgluconeogenesis in liver. When the disease cannot be controlledeffectively through diet and exercise, insulin or oral hypoglycemicdrugs for treatment are needed. At present, hypoglycemic drugs comprisebiguanides, sulfonylureas, insulin sensitizers, glinides, α-glucosidaseinhibitors and DPP-IV (dipeptidyl peptidase IV) inhibitors, etc.However, these current hypoglycemic drugs have shortcomings. Biguanidescan cause lactic acidosis. Sulfonylureas can result in severehypoglycemia. Improper use of glinides can also cause hypoglycemia.Insulin sensitizers can lead to edema, heart failure and weight gain.α-Glucosidase inhibitors can cause abdominal bloating and diarrhea.DPP-IV inhibitors need to combine with metformin to achieve the desiredeffect of hypoglycemia. Therefore, there is an urgent need to developnovel, safer, and more effective hypoglycemic agents.

It has been found by research that glucose transporter proteins are aclass of carrier proteins embedded in the cell membrane for transportingglucose. Glucose must be in virtue of glucose transporter protein tocross lipid bilayer structure of cell membranes. Glucose transporterproteins are divided into two categories. The first category includessodium-dependent glucose transporters (SGLTs), and the other categoryincludes glucose transporters (GLUTs). Two major family members of SGLTsare SGLT1 and SGLT2. SGLT1 is mainly distributed in small intestine,kidney, heart and windpipe, predominantly expressed in the intestinalbrush border and the S3 segment of the renal proximal tubule, and a fewexpressed in heart and windpipe, and transports glucose and galactosewith a sodium to glucose ratio of 2:1. While SGLT2 is mainly distributedin kidney, predominantly expressed in the S1 segment of the renalproximal tubule, and transports glucose with a sodium to glucose ratioof 1:1. In biological bodies, glucose is transported by SGLTs throughactive transport against a concentration gradient with simultaneousenergy consumption. While glucose is transported by GLUTs throughfacilitated diffusion along a concentration gradient without energyconsumption in the transport process. Research indicates that normallyplasma glucose is filtered in the kidney glomeruli in which 90% ofglucose in the early S1 segment of the renal tubule is activelytransported to epithelial cells by SGLT2 and 10% of glucose in thedistal S3 segment of the renal tubule is actively transported toepithelial cells by SGLT1, and then transported to peripheral capillarynetwork by GLUT of epithelial basement membrane accomplishingreabsorption of glucose by renal tubules. Hence, SGLTs is the firststage in regulation of glucose metabolism in cells, and an ideal targetfor treating diabetes effectively. Inhibiting SGLTs would not influencethe normal anti-regulatory mechanism of glucose and cause the risk ofhypoglycemia. Meanwhile, lowering blood glucose through an increase ofrenal glucose excretion could promote weight loss in obese patients. Ithas also been found by research that the mechanism of action of SGLTsinhibitors is independent of pancreatic β cell dysfunction or the degreeof insulin resistance. Therefore, the efficacy of SGLTs inhibitors willnot decrease with the severe insulin resistance or β-cell failure. SGLTsinhibitors could be used alone or in combination with other hypoglycemicagents, through mechanism complementation to better exert hypoglycemiceffect. Therefore, SGLTs inhibitors are ideal and novel hypoglycemicagents.

In addition, it has also been found by research that SGLTs inhibitorscan be used for treating diabetes-related complications. Such asretinopathy, neuropathy, kidney disease, insulin resistance caused byglucose metabolic disorder, hyperinsulinemia, hyperlipidemia, obesity,and so on. Meanwhile, SGLTs inhibitors can also be used in combinationwith current treatment regimens, such as sulphonamides,thiazolidinedione, metformin, and insulin, etc, which can reduce thedose without impacting on the effectiveness of the medicine, and therebyavoid or reduce side effects, and improve patient compliance.

At present, research is mainly focused on the discovery of selectiveSGLT2 inhibitors. Most SGLTs inhibitors currently in clinical trials,such as dapagliflozin, canagliflozin and empagliflozin, are selectiveSGLT2 inhibitors. However, recent clinical trial results indicate thatSGLT1 inhibitors can exhibit greater benefits provided by inhibitingglucose reabsorption (US Patent Application Publication No.US20110218159). According to reports, patients with congenital SGLT1abnormalities have insufficient absorption of glucose and galactose,which provides a factual basis for reducing carbohydrate absorption byinhibiting SGLT1 activity. In addition, in OLETF rats and rats sufferingfrom strepturease-induced diabetes symptoms, the mRNA and protein ofSGLT1 are increased, and glucose absorption is accelerated. Therefore,blocking SGLT1 activity can inhibit the absorption of carbohydrates suchas glucose in the small intestine, and subsequently prevent the rise ofblood glucose levels. In particular, delaying the absorption of glucosebased on the above mechanism can effectively normalize postprandialhyperglycemia. In addition, SGLT1 inhibitors have the ability toincrease glucagon-like peptide-1 (GLP-1) levels (Moriya, R. et al., Am JPhysiol Endorinol Metab, 297: E1358-E1365 (2009)).

In summary, SGLT1 inhibitors have a good prospect as novel antidiabeticdrugs.

SUMMARY OF THE INVENTION

The present invention provides a class of compounds withsignificant/excellent SGLTs inhibitory activity, especially SGLT1inhibitory activity, for improving the intestinal environment; or forthe treatment of diabetes, insulin resistance, hyperglycemia,hyperinsulinemia, hyperlipidemia, obesity, syndrome X, atherosclerosis,cardiovascular disease, congestive heart failure, hypomagnesemia,hyponatremia, renal failure, disorders related to blood concentration,constipation, high blood pressure and their complication. The presentinvention also provides methods of preparing these compounds,pharmaceutical compositions comprising these compounds, and methods ofusing these compounds and compositions to prepare medicaments for theabove-mentioned diseases in mammals, especially humans. Compared withthe existing similar compounds, the compounds of the present inventionnot only have better pharmacological activity, but also have better invivo metabolic kinetic properties and in vivo pharmacodynamicproperties. Specifically, the compounds of the present invention haveexcellent SGLT1 inhibitory activity, and therefore have excellent bloodglucose lowering and urinary glucose excretion effects. Therefore, thecompound provided by the present invention has better druggabilitycompared with the existing similar compounds.

In one aspect, the invention relates to a compound having Formula (I) ora stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, ametabolite, a pharmaceutically acceptable salt, a dimer, a trimer or aprodrug thereof,

wherein,

L is —(CR^(a)R^(b))_(q)—, —CH═CH—(CR^(a)R^(b))_(p)—,—O—(CR^(a)R^(b))_(p)—, —NH—(CR^(a)R^(b))_(p)—, —S—(CR^(a)R^(b))_(p)—,—S(═O)—(CR^(a)R^(b))_(p)— or —S(═O)₂—(CR^(a)R^(b))_(p)—;

q is 1, 2, 3, 4, 5 or 6;

p is 0, 1, 2, 3, 4, 5 or 6;

each R^(a) and R^(b) is independently H, D, F, Cl, Br, I, CN, NO₂, OH,NH₂, —C(═O) OH, —SH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ haloalkoxy, C₃₋₆cycloalkyl or 3-6 membered heterocyclyl; or, R^(a) and R^(b) togetherwith the carbon atom to which they are attached, form a C₃₋₆ carbocycleor a 3-6 membered heterocycle;

R¹ is H, D, F, Cl, Br, I, OH, CN, NO₂, NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylthio, C₃₋₆ cycloalkyl or C₃₋₆cycloalkyl-C₁₋₄ alkylene, wherein each of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylthio, C₃₋₆ cycloalkyl and C₃₋₆cycloalkyl-C₁₋₄ alkylene is independently unsubstituted or substitutedwith 1, 2, 3 or 4 substituents, and the substituent is independentlyselected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino or C₁₋₆ haloalkoxy;

each of R² and R³ is independently H, D, CN, OH, NH₂, —SH, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆alkylamino, C₃₋₆ cycloalkyl or 3-6 membered heterocyclyl, wherein eachC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio,C₁₋₆ alkylamino, C₃₋₆ cycloalkyl and 3-6 membered heterocyclyl isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, ═O, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino or C₁₋₆ haloalkoxy;

or, R² and R³ together with the carbon atom to which they are attached,form carbonyl, or R² and R³, together with the carbon atom to which theyare attached form a C₃₋₆ carbocycle or a 3-6 membered heterocycle,wherein each of C₃₋₆ carbocycle and 3-6 membered heterocycle isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, ═O, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino or C₁₋₆ haloalkoxy;

R⁴ is H, D, —OR^(4a) or —SR^(4b);

each of R^(4a) and R^(4b) is independently H, D, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, 5-6 membered heterocyclyl,(5-6 membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkylene, 5-6 membered heteroaryl or (5-6 membered heteroaryl)-C₁₋₄alkylene, wherein each C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄alkylene, 5-6 membered heterocyclyl, (5-6 membered heterocyclyl)-C₁₋₄alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5-6 membered heteroaryland (5-6 membered heteroaryl)-C₁₋₄ alkylene is independentlyunsubstituted or substituted with 1, 2, 3 or 4 substituents, and thesubstituent is independently selected from D, F, Cl, Br, I, CN, NO₂, OH,NH₂, —C(═O) OH, —SH, ═O, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆alkylamino or C₁₋₆ haloalkoxy;

each R¹⁰ is H, D, F, Cl, Br, I, OH, CN, NO₂, NH₂, C₁₋₆ alkyl or C₁₋₆alkoxy;

R⁵ is H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, 3-8 memberedheterocyclyl, C₆₋₁₀ aryl or 5-8 membered heteroaryl, wherein each ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl,C₆₋₁₀ aryl and 5-8 membered heteroaryl is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O,—C(═O) OH, —C(═O) NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ haloalkoxy, C₃₋₆cycloalkyl, 5-6 membered heterocyclyl, C₆₋₁₀ aryl or 5-6 memberedheteroaryl;

each of R⁶ and R⁷ is independently H, D, F, Cl, Br, I, CN, NO₂, OH, NH₂,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl, C₆₋₁₀ aryl or5-8 membered heteroaryl, wherein each C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkylamino, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₈ cycloalkyl, 3-8membered heterocyclyl, C₆₋₁₀ aryl and 5-8 membered heteroaryl isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, ═O, —C(═O) OH, —C(═O) NH₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino,C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, 5-6 membered heterocyclyl, C₆₋₁₀ arylor 5-6 membered heteroaryl;

or, R⁶ and R⁷ together with the carbon atom to which they are attached,form a C₃₋₈ carbocycle, a 3-8 membered heterocycle, a C₆₋₁₀ aromaticring or a 5-8 membered heteroaromatic ring, wherein each of C₃₋₈carbocycle, 3-8 membered heterocycle, C₆₋₁₀ aromatic ring and 5-8membered heteroaromatic ring is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O,—C(═O) OH, —C(═O) NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino or C₁₋₆ haloalkoxy;

or R⁵ and R⁶ together with the atom to which they are attached, or R⁵and R⁷ together with the atom to which they are attached, form a 3-8membered heterocycle or a 5-8 membered heteroaromatic ring, wherein each3-8 membered heterocycle and 5-8 membered heteroaromatic ring isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, ═O, —C(═O) OH, —C(═O) NH₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino orC₁₋₆ haloalkoxy;

each of R⁸ and R⁹ is independently H, D, R^(e)O—C₁₋₄ alkylene,R^(d)R^(c)N—C₁₋₄ alkylene, C₁₋₈ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl,C₃₋₈ cycloalkyl-C₁₋₄ alkylene, 3-8 membered heterocyclyl, (3-8 memberedheterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5-8membered heteroaryl or (5-8 membered heteroaryl)-C₁₋₄ alkylene, whereineach C₁₋₈ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₄alkylene, 3-8 membered heterocyclyl, (3-8 membered heterocyclyl)-C₁₋₄alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5-8 membered heteroaryland (5-8 membered heteroaryl)-C₁₋₄ alkylene is independentlyunsubstituted or substituted with 1, 2, 3 or 4 substituents, and thesubstituent is independently selected from D, F, Cl, Br, I, CN, NO₂, ═O,—OR^(e), —NR^(c)R^(d), —C(═O)OR^(e), —C(═O) NHR^(f), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino orC₁₋₆ haloalkoxy;

or, R⁸ and R⁹ together with the nitrogen atom to which they areattached, form a 3-8 membered heterocycle or a 5-8 memberedheteroaromatic ring, wherein each of 3-8 membered heterocycle and 5-8membered heteroaromatic ring is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, ═O, —OR^(e),—NR^(c)R^(d), —C(═O)OR^(e), —C(═O)NHR^(f), C₁₋₆ alkyl, C₂₋₆ alkenyl,C²⁻⁶ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino or C₁₋₆haloalkoxy;

each R^(c), R^(d), R^(e) and R^(f) is independently H, D, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₄ alkylene, 3-8membered heterocyclyl, (3-8 membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5-8 membered heteroaryl or (5-8 memberedheteroaryl)-C₁₋₄ alkylene, wherein each C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₄ alkylene, 3-8 membered heterocyclyl,(3-8 membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkylene, 5-8 membered heteroaryl and (5-8 membered heteroaryl)-C₁₋₄alkylene is independently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, —NH₂, ═O, —C(═O)OH, —C(═O)NH₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino orC₁₋₆ haloalkoxy;

or, R^(c) and R^(d) together with the nitrogen atom to which they areattached, form a 3-8 membered heterocycle or a 5-8 memberedheteroaromatic ring, wherein each of 3-8 membered heterocycle and 5-8membered heteroaromatic ring is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, ═O, OH, —NH₂,—C(═O)OH, —C(═O)NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C²⁻⁶ alkynyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino or C₁₋₆ haloalkoxy;

n is 0, 1, 2 or 3;

t is 0, 1, 2, 3, 4, 5 or 6; with the proviso that when R⁵ and R⁸ areboth H, and R⁹ is

t is not 0.

In other embodiments, the present invention relates to a compound havingformula (II), or a stereoisomer, a geometric isomer, a tautomer, anN-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, adimer, a trimer or a prodrug thereof,

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, n and t have thedefinitions described in the present invention.

In other embodiments, R¹ is H, D, F, Cl, Br, I, OH, CN, NO₂, NH₂,methyl, ethyl, n-propyl, isopropyl, propenyl, propynyl, methoxy, ethoxy,hydroxymethyl, trifluoromethyl, trifluoroethyl, monofluoromethyl,trifluoromethoxy, difluoromethoxy, methylamino, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cyclopropyl-methylene, wherein each ofmethyl, ethyl, n-propyl, isopropyl, propenyl, propynyl, methoxy, ethoxy,hydroxymethyl, trifluoroethyl, monofluoromethyl, difluoromethoxy,methylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcyclopropyl-methylene is independently unsubstituted or substituted with1, 2, 3, or 4 substituents, and the substituent is independentlyselected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, methyl,ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy,methylamino, trifluoromethoxy or difluoromethoxy.

In some embodiments, each of R² and R³ is independently H, D, CN, OH,NH₂, —SH, methyl, ethyl, n-propyl, isopropyl, vinyl, propynyl, methoxy,ethoxy, methylthio, methylamino, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or 5-6 membered heterocyclyl, wherein each methyl, ethyl,n-propyl, isopropyl, vinyl, propynyl, methoxy, ethoxy, methylthio,methylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 5-6membered heterocyclyl is independently unsubstituted or substituted with1, 2, 3 or 4 substituents, and the substituent is independently selectedfrom D, F, Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, ═O, methyl,ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethyloxy,methylamino, trifluoromethoxy or difluoromethoxy;

or, R² and R³, together with the carbon atom to which they are attached,form carbonyl;

or, R² and R³ together with the carbon atom to which they are attached,form cyclopropane, cyclobutane, cyclopentane, cyclohexane or a 5-6membered heterocycle, wherein each of cyclopropane, cyclobutane,cyclopentane, cyclohexane and a 5-6 membered heterocycle isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, ═O, methyl, ethyl,n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, methylamino,trifluoromethoxy or difluoromethoxy.

In some embodiments, R⁴ is H, D, —OR^(4a) or —SR^(4b);

each of R^(4a) and R^(4b) is independently H, D, methyl, ethyl,n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,C₃₋₆ cycloalkyl-C₁₋₂ alkylene, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, (5-6 membered heterocyclyl)-C₁₋₂ alkylene, phenyl,phenyl-C₁₋₂ alkylene, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinylor (5-6 membered heteroaryl)-C₁₋₂ alkylene, wherein each methyl, ethyl,n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,C₃₋₆ cycloalkyl-C₁₋₂ alkylene, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, (5-6 membered heterocyclyl)-C₁₋₂ alkylene, phenyl,phenyl-C₁₋₂ alkylene, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyland (5-6 membered heteroaryl)-C₁₋₂ alkylene is independentlyunsubstituted or substituted with 1, 2, 3, or 4 substituents, and thesubstituent is independently selected from D, F, Cl, Br, I, CN, NO₂, OH,NH₂, —C(═O) OH, —SH, ═O, methyl, ethyl, n-propyl, isopropyl,trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxy ordifluoromethoxy.

In other embodiments, R¹⁰ is H, D, F, Cl, Br, I, OH, CN, NO₂, NH₂,methyl, ethyl, n-propyl, isopropyl, methoxy or ethoxy.

In other embodiments, R⁵ is H, D, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl, 5-6 membered heterocyclyl, C₆₋₁₀ aryl or 5-6 memberedheteroaryl, wherein each of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl,5-6 membered heterocyclyl, C₆₋₁₀ aryl and 5-6 membered heteroaryl isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, ═O, —C(═O) OH, —C(═O) NH₂, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, 5-6 membered heterocyclyl, C₆₋₁₀ arylor 5-6 membered heteroaryl;

each of R⁶ and R⁷ is independently H, D, F, Cl, Br, I, CN, NO₂, OH, NH₂,C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, C₃₋₆ cycloalkyl, 5-6 membered heterocyclyl, C₆₋₁₀ aryl or5-6 membered heteroaryl, wherein each C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylamino, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, 5-6membered heterocyclyl, C₆₋₁₀ aryl and 5-6 membered heteroaryl isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, ═O, —C(═O) OH, —C(═O) NH₂, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, 5-6 membered heterocyclyl, C₆₋₁₀ arylor 5-6 membered heteroaryl;

or, R⁶ and R⁷ together with the carbon atom to which they are attached,form a C₃₋₆ carbocycle, a 5-6 membered heterocycle, a C₆₋₁₀ aromaticring or a 5-6 membered heteroaromatic ring, wherein each of C₃₋₆carbocycle, 5-6 membered heterocycle, C₆₋₁₀ aromatic ring and 5-6membered heteroaromatic ring is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O,—C(═O) OH, —C(═O) NH₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino or C₁₋₄ haloalkoxy;

or R⁵ and R⁶ together with the atom to which they are attached, or R⁵and R⁷ together with the atom to which they are attached, form a 3-6membered heterocycle or a 5-6 membered heterocycle, wherein each 3-6membered heterocycle and 5-6 membered heterocycle is independentlyunsubstituted or substituted with 1, 2, 3 or 4 substituents, and thesubstituent is independently selected from D, F, Cl, Br, I, CN, NO₂, OH,NH₂, ═O, —C(═O) OH, —C(═O) NH₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino or C₁₋₄ haloalkoxy.

In still other embodiments, R⁵ is H, D, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl,piperidinyl, morpholinyl, thiomorpholyl, piperazinyl, phenyl, furyl,pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl,pyridazinyl or pyrimidinyl, wherein each of methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl,piperidinyl, morpholinyl, thiomorpholyl, piperazinyl, phenyl, furyl,pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl,pyridazinyl and pyrimidinyl is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O,—C(═O) OH, —C(═O) NH₂, methyl, ethyl, n-propyl, isopropyl, vinyl,ethynyl, trifluoromethyl, methoxy, ethoxy, methylamino,trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentylor phenyl;

each of R⁶ and R⁷ is independently H, D, F, Cl, Br, I, CN, NO₂, OH, NH₂,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,methoxy, ethoxy, methylamino, trifluoromethyl, trifluoromethoxy,difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl,1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl orpyrimidinyl, wherein each methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, methoxy, ethoxy, methylamino, difluoromethoxy,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholyl,piperazinyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl,thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, ═O, —C(═O) OH, —C(═O) NH₂, methyl, ethyl,n-propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, methoxy, ethoxy,methylamino, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl,cyclopentyl or phenyl;

or, R⁶ and R⁷ together with the carbon atom to which they are attached,form cyclopropane, cyclobutane, cyclopentane, cyclohexane, pyrrolidine,tetrahydrofuran, tetrahydrothiophene, tetrahydropyran,tetrahydrothiopyran, piperidine, morpholine, thiomorpholine, piperazine,benzene ring, furan, pyrrole, pyridine, pyrazole, imidazole, triazole,tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole, thiophene,pyrazine, pyridazine or pyrimidine, wherein each of cyclopropane,cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahydrofuran,tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, piperidine,morpholine, thiomorpholine, piperazine, benzene ring, furan, pyrrole,pyridine, pyrazole, imidazole, triazole, tetrazole, oxazole, oxadiazole,1,3,5-triazine, thiazole, thiophene, pyrazine, pyridazine and pyrimidineis independently unsubstituted or substituted with 1, 2, 3, or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, ═O, —C(═O) OH, —C(═O) NH₂, methyl, ethyl,n-propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, methoxy, ethoxy,methylamino, trifluoromethoxy or difluoromethoxy;

or R⁵ and R⁶ together with the atom to which they are attached, or R⁵and R⁷ together with the atom to which they are attached, formaziridine, azetidine, pyrrolidine, pyrazolidine, imidazolidine,oxazolidine, thiazolidine, piperidine, morpholine, thiomorpholine,piperazine, pyrrole, pyridine, pyrazole, imidazole, triazole, tetrazole,oxazole, oxadiazole, 1,3,5-triazine, thiazole, pyrazine, pyridazine orpyrimidine, wherein each aziridine, azetidine, pyrrolidine,pyrazolidine, imidazolidine, oxazolidine, thiazolidine, piperidine,morpholine, thiomorpholine, piperazine, pyrrole, pyridine, pyrazole,imidazole, triazole, tetrazole, oxazole, oxadiazole, 1,3,5-triazine,thiazole, pyrazine, pyridazine and pyrimidine is independentlyunsubstituted or substituted with 1, 2, 3, or 4 substituents, and thesubstituent is independently selected from D, F, Cl, Br, I, CN, NO₂, OH,NH₂, ═O, —C(═O) OH, —C(═O) NH₂, methyl, ethyl, n-propyl, isopropyl,vinyl, ethynyl, trifluoromethyl, methoxy, ethoxy, methylamino,trifluoromethoxy or difluoromethoxy.

In other embodiments, each of R⁸ and R⁹ is independently H, D,R^(c)O—C₁₋₄ alkylene, R^(d)R^(c)N—C₁₋₄alkylene, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene, 5-6 memberedheterocyclyl, (5-6 membered heterocyclyl)-C₁₋₂ alkylene, C₆₋₁₀ aryl,C₆₋₁₀ aryl-C₁₋₂ alkylene, 5-6 membered heteroaryl or (5-6 memberedheteroaryl)-C₁₋₂ alkylene, wherein each C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene, 5-6 membered heterocyclyl,(5-6 membered heterocyclyl)-C₁₋₂ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₂alkylene, 5-6 membered heteroaryl and (5-6 membered heteroaryl)-C₁₋₂alkylene is independently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, ═O, —OR^(e), —NR^(c)R^(d), —C(═O)OR^(e), —C(═O)NHR^(f), C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ alkylamino or C₁₋₄ haloalkoxy;

or, R⁸ and R⁹ together with the nitrogen atom to which they areattached, form a 3-6 membered heterocycle or a 5-6 memberedheteroaromatic ring, wherein each of 3-6 membered heterocycle and 5-6membered heteroaromatic ring is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, ═O, —OR^(e),—NR^(c)R^(d), —C(═O)OR^(e), —C(═O)NHR^(f), C₁₋₄ alkyl, C₂₋₄ alkenyl,C²⁻⁴ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino or C₁₋₄haloalkoxy.

In still other embodiments, each of R⁸ and R⁹ is independently H, D,R^(d)R^(c)N—C₁₋₄ alkylene, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl, n-hexyl, trifluoromethyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene,pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,thiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, (5-6 membered heterocyclyl)-C₁₋₂ alkylene, phenyl, C₆₋₁₀aryl-C₁₋₂ alkylene, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl,thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl or (5-6 memberedheteroaryl)-C₁₋₂ alkylene, wherein each methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C₃₋₆ cycloalkyl-C₁₋₂alkylene, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,thiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, (5-6 membered heterocyclyl)-C₁₋₂ alkylene, phenyl, C₆₋₁₀aryl-C₁₋₂ alkylene, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl,thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl and (5-6membered heteroaryl)-C₁₋₂ alkylene is independently unsubstituted orsubstituted with 1, 2, 3, or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, ═O, —OH,—NR^(c)R^(d), —C(═O)OH, —C(═O)NH₂, methyl, ethyl, n-propyl, vinyl,ethynyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxyor difluoromethoxy;

or, R⁸ and R⁹ together with the nitrogen atom to which they areattached, form aziridine, azetidine, pyrrolidine, pyrazolidine,imidazolidine, oxazolidine, thiazolidine, piperidine, morpholine,thiomorpholine, piperazine, pyrazole, imidazole, triazole, tetrazole,oxazole, oxadiazole, 1,3,5-triazine, thiazole, pyrazine, pyridazine orpyrimidine, wherein each of aziridine, azetidine, pyrrolidine,pyrazolidine, imidazolidine, oxazolidine, thiazolidine, piperidine,morpholine, thiomorpholine, piperazine, pyrazole, imidazole, triazole,tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole, pyrazine,pyridazine and pyrimidine is independently unsubstituted or substitutedwith 1, 2, 3, or 4 substituents, and the substituent is independentlyselected from D, F, Cl, Br, I, CN, NO₂, ═O, —OH, —NR^(c)R^(d), —C(═O)OH, —C(═O) NH₂, methyl, ethyl, n-propyl, vinyl, ethynyl,trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxy ordifluoromethoxy.

In some embodiments, each R^(c), R^(d), R^(e) and R^(f) is independentlyH, D, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂alkylene, 5-6 membered heterocyclyl, (5-6 membered heterocyclyl)-C₁₋₂alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₂ alkylene, 5-6 membered heteroarylor (5-6 membered heteroaryl)-C₁₋₂ alkylene, wherein each C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene, 5-6membered heterocyclyl, (5-6 membered heterocyclyl)-C₁₋₂ alkylene, C₆₋₁₀aryl, C₆₋₁₀ aryl-C₁₋₂ alkylene, 5-6 membered heteroaryl and (5-6membered heteroaryl)-C₁₋₂ alkylene is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, —NH₂, ═O,—C(═O)OH, —C(═O)NH₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino or C₁₋₄ haloalkoxy;

or, R^(c) and R^(d) together with the nitrogen atom to which they areattached, form a 3-6 membered heterocycle or a 5-6 memberedheteroaromatic ring, wherein each of 3-6 membered heterocycle and 5-6membered heteroaromatic ring is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, ═O, OH, —NH₂,—C(═O)OH, —C(═O)NH₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C²⁴ alkynyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino or C₁₋₄ haloalkoxy.

In still other embodiments, each R^(c), R^(d), R^(e) and R^(f) isindependently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene, pyrrolidinyl,pyrazolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, (5-6 membered heterocyclyl)-C₁₋₂ alkylene, phenyl,phenyl-C₁₋₂ alkylene, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl,thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl or (5-6 memberedheteroaryl)-C₁₋₂ alkylene, wherein each methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene, pyrrolidinyl,pyrazolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, (5-6 membered heterocyclyl)-C₁₋₂ alkylene, phenyl,phenyl-C₁₋₂ alkylene, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl,thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl and (5-6membered heteroaryl)-C₁₋₂ alkylene is independently unsubstituted orsubstituted with 1, 2, 3, or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, —NH₂, ═O,—C(═O) OH, —C(═O) NH₂, methyl, ethyl, n-propyl, isopropyl, vinyl,ethynyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxyor difluoromethoxy;

or, R^(c) and R^(d) together with the nitrogen atom to which they areattached, form aziridine, azetidine, pyrrolidine, pyrazolidine,imidazolidine, oxazolidine, thiazolidine, piperidine, morpholine,thiomorpholine, piperazine, pyrazole, imidazole, triazole, tetrazole,oxazole, oxadiazole, 1,3,5-triazine, thiazole, pyrazine, pyridazine orpyrimidine, wherein each of aziridine, azetidine, pyrrolidine,pyrazolidine, imidazolidine, oxazolidine, thiazolidine, piperidine,morpholine, thiomorpholine, piperazine, pyrazole, imidazole, triazole,tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole, pyrazine,pyridazine and pyrimidine is independently unsubstituted or substitutedwith 1, 2, 3, or 4 substituents, and the substituent is independentlyselected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O, —C(═O) OH, —C(═O)NH₂, methyl, ethyl, n-propyl, isopropyl, vinyl, ethynyl,trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxy ordifluoromethoxy.

In other aspect, provided herein is a pharmaceutical compositioncomprising the compound disclosed herein.

In some embodiments, the pharmaceutical composition of the presentinvention further comprises a pharmaceutically acceptable carrier,excipient, adjuvant, vehicle or a combination thereof.

In some embodiments, the pharmaceutical composition of the presentinvention further comprises one or more other additional therapeuticagents, wherein the other additional therapeutic agent is selected froman anti-diabetic drug, an anti-hyperglycemic drug, an anti-obesity drug,an anti-hypertensive drug, an appetite suppressant drug, alipid-lowering drug, or a combination thereof.

In other embodiments, each anti-diabetic and anti-hyperglycemic drug ofthe present invention is independently selected from a SGLT2 inhibitor,a biguanide drug, a sulfonylurea drug, a glucosidase inhibitor, a PPARagonist (peroxisome proliferator-activated receptor agonist), a αP2inhibitor (fat cell fatty Acid binding protein inhibitor), a PPARα/γdual activator (peroxisome proliferator-activated receptor α/γ dualactivator), a dipeptidyl peptidase IV inhibitor, a glinides drug, aninsulin, a glucagon-like peptide-1 inhibitor, a PTP1B inhibitor (proteintyrosine phosphatase 1B inhibitor), a glycogen phosphorylase inhibitor,a glucose-6-phosphatase inhibitor or a combination thereof.

In other embodiments, the anti-obesity drug of the present invention isselected from a central anti-obesity drug, a MCH (black pigmentconcentrating hormone) receptor antagonist, a neuropeptide Y receptorantagonist, a cannabinoid receptor antagonist, a cerebrointestinalpeptide antagonist, a lipase inhibitor, a β3 agonist, a 11β-HSD1 (11βhydroxysteroid dehydrogenase 1) inhibitor, a DGAT-1 (diacylglycerolacyltransferase 1) inhibitor, a peptide appetite inhibitor, acholecystokinin agonist, a feeding inhibitor or a combination thereof.

In other embodiments, the lipid-lowering drug of the present inventionis selected from a MTP inhibitor (microsomal triglyceride transferprotein inhibitor), a HMGCoA reductase inhibitor (hydroxymethylglutarylcoenzyme A reductase inhibitor), a squalene synthase inhibitor, abetinic acid-type hypolipidemic drug (also known as fibratehypolipidemic drug), an ACAT inhibitor (acetylcholesterolacetyltransferase inhibitor), a lipoxygenase inhibitor, a cholesterolabsorption inhibitor, an ileum sodium ion/bile acid co-transporterinhibitor, an up-regulator of LDL receptor activity, a nicotinichypolipidemic drug, a bile acid chelate, or a combination thereof.

In still other embodiments, the lipid-lowering drug is pravastatin,simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin,rosuvastatin or a combination thereof.

In other aspect, provided herein is use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for inhibiting SGLT1.

In other aspect, provided herein is use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for improving the intestinal environment.

In other aspect, provided herein is use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for preventing or treating a disease, lessening a diseasesymptom or delaying the progression or onset of a disease, wherein thedisease is diabetes, diabetic complication, insulin resistance,hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity, syndrome X,atherosclerosis, cardiovascular disease, congestive heart failure,hypomagnesemia, hyponatremia, renal failure, disorders related to bloodconcentration, constipation, or high blood pressure.

In another aspect, provided herein is a method of inhibiting SGLT1,comprising administering a therapeutically effective amount of thecompound of the invention or the pharmaceutical composition of theinvention to a subject.

In another aspect, provided herein is a method of improving theintestinal environment, comprising administering a therapeuticallyeffective amount of the compound of the invention or the pharmaceuticalcomposition of the invention to a subject.

In another aspect, provided herein is a method of preventing or treatinga disease, lessening a disease symptom or delaying the progression oronset of a disease in a subject comprising administering to the subjecta therapeutically effective amount of the compound of the invention orthe pharmaceutical composition of the invention, wherein the disease isdiabetes, diabetic complication, insulin resistance, hyperglycemia,hyperinsulinemia, hyperlipidemia, obesity, syndrome X, atherosclerosis,cardiovascular disease, congestive heart failure, hypomagnesemia,hyponatremia, renal failure, disorders related to blood concentration,constipation, or high blood pressure.

In other aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in inhibiting SGLT1.

In other aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in improving the intestinalenvironment.

In other aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in preventing or treating adisease, lessening a disease symptom or delaying the progression oronset of a disease, wherein the disease is diabetes, diabetescomplications, insulin resistance, hyperglycemia, hyperinsulinemia,hyperlipidemia, obesity, syndrome X, atherosclerosis, cardiovasculardisease, congestive heart failure, hypomagnesemia, hyponatremia, renalfailure, disorders related to blood concentration, constipation, or highblood pressure.

In some embodiments, the diabetic complication is diabetic retinopathy,diabetic neuropathy or diabetic nephropathy.

In some embodiments, the hyperlipidemia is hypertriglyceridemia.

The foregoing merely summarizes certain aspects disclosed herein and isnot intended to be limiting in nature. These aspects and other aspectsand embodiments are described more fully below.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a glucopyranosyl derivative, preparationprocesses and pharmaceutical uses thereof. Skilled in the art can learnfrom this article to properly improve the process parameters. Ofparticular note is that all similar substitutions and modifications tothe skilled person is obvious, and they are deemed to be included in thepresent invention.

Definitions and General Terminology

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. The invention is intended to cover allalternatives, modifications, and equivalents which may be includedwithin the scope of the present invention. One skilled in the art willrecognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention. The present invention is by no means limited to the methodsand materials described herein. In the event that one or more of theincorporated literature, patents, and similar materials differs from orcontradicts this application, including but not limited to definedterms, term usage, described techniques, or the like, this applicationcontrols.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one skilled in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference in their entirety. Asused herein, the following definitions shall apply unless otherwiseindicated. For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, and the Handbook of Chemistry and Physics, 75th Ed. 1994.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and Smith et al., “March's Advanced Organic Chemistry”,John Wiley & Sons, New York: 2007, the entire contents of which arehereby incorporated by reference.

The grammatical articles “a”, “an” and “the”, as used herein, areintended to include “at least one” or “one or more” unless otherwiseindicated herein or clearly contradicted by the context. Thus, thearticles used herein refer to one or more than one (i.e. at least one)articles of the grammatical objects. By way of example, “a component”means one or more components, and thus, possibly, more than onecomponent is contemplated and may be employed or used in animplementation of the described embodiments.

Unless otherwise stated, the terms used in the specification and claimsof the present invention have the following definitions.

The term “comprise” is an open expression, it means comprising thecontents disclosed herein, but don't exclude other contents.

As described herein, compounds disclosed herein may optionally besubstituted with one or more substituents, such as are illustratedgenerally below, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted”. The term “optionally” or “optional”means that the subsequently described event or condition can but doesnot necessarily occur, and the description includes the situation inwhich the event or condition occurs, and the situation in which theevent or condition does not occur. In general, the term “optionally”whether or not preceding the term “substituted” means that one or morehydrogen atoms in a given structure are unsubstituted or substitutedwith a specific substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group. When more than one position in a given structure can besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at eachposition. The substituents described herein may be, but not limited to,D, F, Cl, Br, I, CN, NO₂, OH, NH₂, oxo (═O), —C(═O) OH, —C(═O) NH₂, —SH,—OR^(e), —NR^(c)R^(d), —C(═O)OR^(e), —C(═O)NHR^(f), alkyl, haloalkyl,alkoxy, alkylamino, alkylthio, haloalkoxy, alkenyl, alkynyl,hydroxyalkyl, cycloalkyl, cycloalkyl-alkylene, carbocyclyl,carbocyclyl-alkylene, heterocyclyl, heterocyclyl-alkylene, aryl,aryl-alkylene, heteroaryl or heteroaryl-alkylene, wherein R^(c), R^(d),R^(e) and R^(f) have the definitions described in this invention.

Furthermore, what need to be explained is that the phrases “each . . .is independently” and “each of . . . and . . . is independently”, unlessotherwise stated, should be broadly understood, which can mean that thespecific options expressed by the same symbol are independent of eachother in different groups; or the specific options expressed by the samesymbol are independent of each other in same groups.

At each part of the present specification, substitutes of compoundsdisclosed herein are disclosed in groups or in ranges. It isspecifically intended that the invention includes each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₈ alkyl” especially refers to independentlydisclosed C₁ alkyl (methyl), C₂ alkyl (ethyl), C₃ alkyl, C₄ alkyl, C₅alkyl, C₆ alkyl, C₇ alkyl and C₈ alkyl; “C₃₋₈ cycloalkyl” meansindependently disclosed C₃ cycloalkyl (cyclopropyl), C₄ cycloalkyl(cyclobutyl), C₅ cycloalkyl (cyclopentyl), C₆ cycloalkyl (cyclohexyl),C₇ cycloalkyl (cycloheptyl) and C₈ cycloalkyl (cyclooctyl); “3-8membered heterocycle (radical)” refers to independently disclosed 3membered heterocycle, 4 membered heterocycle, 5 membered heterocycle, 6membered heterocycle, 7 membered heterocycle and 8 membered heterocycle.

At various places in the present specification, linking substituents aredescribed. Where the structure clearly requires a linking group, theMarkush variables listed for that group are understood to be linkinggroups. For example, if the structure requires a linking group and theMarkush group definition for that variable lists “alkyl” or “aryl” thenit is understood that the “alkyl” or “aryl” represents a linkingalkylene group or arylene group, respectively.

The term “alkyl” or “alkyl group” as used herein refers to a saturatedlinear or branched monovalent hydrocarbon radical containing 1 to 20carbon atoms. Unless otherwise specified, the alkyl group contains 1-20carbon atoms. In some embodiments, the alkyl group contains 1-12 carbonatoms. In some embodiments, the alkyl group contains 1-10 carbon atoms.In other embodiments, the alkyl group contains 1-9 carbon atoms. Inother embodiments, the alkyl group contains 1-8 carbon atoms. In otherembodiments, the alkyl group contains 1-6 carbon atoms, i.e., C₁₋₆alkyl. In still other embodiments, the alkyl group contains 1-4 carbonatoms, i.e., C₁₋₄ alkyl. In yet other embodiments, the alkyl groupcontains 1-3 carbon atoms, i.e., C₁₋₃ alkyl. In still yet otherembodiments, the alkyl group contains 1-2 carbon atoms, i.e., C₁₋₂alkyl.

Some non-limiting examples of the alkyl group include, methyl (Me,—CH₃), ethyl (Et, —CH₂CH₃), n-propyl (n-Pr, —CH₂CH₂CH₃), isopropyl(i-Pr, —CH(CH₃)₂), n-butyl (n-Bu, —CH₂CH₂CH₂CH₃), isobutyl (i-Bu,—CH₂CH(CH₃)₂), sec-butyl (s-Bu, —CH(CH₃)CH₂CH₃), tert-butyl (t-Bu,—C(CH₃)₃), n-pentyl (—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃),3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃),3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂),2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), n-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃),2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, n-heptyl and n-octyl, etc.Wherein, the alkyl group may be optionally substituted with one or moresubstituents disclosed herein.

The term “alkyl” or the prefix “alk-” used in the present invention isinclusive of both straight chain and branched saturated carbon chain.

The term “alkylene” refers to a saturated divalent hydrocarbon groupderived from a straight or branched chain saturated hydrocarbon by theremoval of two hydrogen atoms. Unless otherwise specified, the alkylenegroup contains 1-12 carbon atoms. In some embodiments, the alkylenegroup contains 1-8 carbon atoms. In other embodiments, the alkylenegroup contains 1-6 carbon atoms. In other embodiments, the alkylenegroup contains 1-4 carbon atoms, i.e., C₁₋₄ alkylene. In still otherembodiments, the alkylene group contains 1-3 carbon atoms, i.e., C₁₋₃alkylene. In yet other embodiments, the alkylene group contains 1-2carbon atoms, i.e., C₁₋₂ alkylene. Such examples include methylene(—CH₂—), ethylene (including —CH₂CH₂— or —CH(CH₃)—), isopropylidene(including —CH(CH₃)CH₂— or —C(CH₃)₂—), n-propylene (including—CH₂CH₂CH₂—, —CH(CH₂CH₃)— or —CH₂CH(CH₃)—), n-butylene (including—CH₂(CH₂)₂CH₂—, —CH(CH₂CH₂CH₃)—, —CH₂CH(CH₂CH₃)—, —CH₂CH₂CH(CH₃)— or—CH(CH₃)CH(CH₃)—), tert-butylene (including —CH(CH(CH₃)₂)—,—CH₂CH(CH₃)CH₂— or —CH₂C(CH₃)₂—), pentylene (e.g., —CH₂(CH₂)₃CH₂—),hexylene (e.g., —CH₂(CH₂)₄CH₂—) and so on. wherein, the alkylene groupmay be optionally substituted with one or more substituents disclosedherein.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical of 2 to 12 carbon atoms with at least one site ofunsaturation, i.e., a carbon-carbon, sp² double bond, wherein thealkenyl radical may be optionally substituted with one or moresubstituents described herein, and includes radicals having “cis” and“trans” orientations, or alternatively, “E” and “Z” orientations. Insome embodiments, the alkenyl contains 2 to 8 carbon atoms. In otherembodiments, the alkenyl contains 2 to 6 carbon atoms, i.e., C₂₋₆alkenyl. In still other embodiments, the alkenyl contains 2 to 4 carbonatoms, i.e., C₂₋₄ alkenyl. Examples of the alkenyl group include, butare not limited to, vinyl (—CH═CH₂), propenyl (—CH₂CH═CH₂, —CH═CHCH₃),butenyl (—CH═CHCH₂CH₃, —CH₂CH═CHCH₃, —CH₂CH₂CH═CH₂, —CH═C(CH₃)₂,—CH═C(CH₃)₂, —CH₂C(CH₃)═CH₂), pentenyl (—CH₂CH₂CH₂CH═CH₂,—CH₂CH₂CH═CHCH₃, —CH₂CH₂CH═CHCH₃, —CH₂CH═CHCH₂CH₃, —CH═CHCH₂CH₂CH₃,—CH₂CH₂C(CH₃)═CH₂, —CH₂CH═C(CH₃)₂, —CH═CHCH(CH₃)₂, —C(CH₂CH₃)═CHCH₃,—CH(CH₂CH₃)CH═CH₂), etc.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical of 2 to 12 carbon atoms with at least one site of unsaturation,i.e., a carbon-carbon, sp triple bond. In some embodiments, the alkynylcontains 2 to 8 carbon atoms. In other embodiments, the alkynyl contains2 to 6 carbon atoms, i.e., C₂₋₆ alkynyl. In still other embodiments, thealkynyl contains 2 to 4 carbon atoms, i.e., C₂₋₄ alkynyl. Somenon-limiting examples of the alkynyl group include ethynyl (—C≡CH),propynyl (including 1-propynyl (—C≡C—CH₃) and propargyl (—CH₂C≡CH)),1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl,1-hexynyl, 1-heptynyl and 1-octynyl, etc. The alkynyl group may beindependently and optionally substituted by one or more substituentsdisclosed herein.

The term “alkoxy” or “alkyloxy” refers to an alkyl group, as previouslydefined, attached to parent molecular moiety via an oxygen atom, i.e.,alkyl-O—. In some embodiments, the alkoxy group contains 1-20 carbonatoms. In some embodiments, the alkoxy group contains 1-10 carbon atoms.In other embodiments, the alkoxy group contains 1-8 carbon atoms. Inother embodiments, the alkoxy group contains 1-6 carbon atoms, i.e.,C₁₋₆ alkoxy. In other embodiments, the alkoxy group contains 1-4 carbonatoms, i.e., C₁₋₄ alkoxy. In still other embodiment, the alkoxy groupcontains 1-3 carbon atoms, i.e., C₁₋₃ alkoxy. In yet other embodiment,the alkoxy group contains 1-2 carbon atoms, i.e., C₁₋₂ alkoxy.

Some non-limiting examples of the alkoxy group include, but are notlimited to, methoxy (MeO, —OCH₃), ethoxy (EtO, —OCH₂CH₃), 1-propoxy(n-PrO, n-propoxy, —OCH₂CH₂CH₃), 2-propoxy (i-PrO, i-propoxy,—OCH(CH₃)₂), 1-butoxy (n-BuO, n-butoxy, —OCH₂CH₂CH₂CH₃),2-methyl-1-propoxy (i-BuO, i-butoxy, —OCH₂CH(CH₃)₂), 2-butoxy (s-BuO,s-butoxy, —OCH(CH₃)CH₂CH₃), 2-methyl-2-propoxy (t-BuO, t-butoxy,—OC(CH₃)₃), 1-pentoxy (n-pentoxy, —OCH₂CH₂CH₂CH₂CH₃), 2-pentoxy(—OCH(CH₃)CH₂CH₂CH₃), 3-pentoxy (—OCH(CH₂CH₃)₂), 2-methyl-2-butoxy(—OC(CH₃)₂CH₂CH₃), 3-methyl-2-butoxy (—OCH(CH₃)CH(CH₃)₂),3-methyl-1-butoxy (—OCH₂CH₂CH(CH₃)₂), 2-methyl-1-butoxy(—OCH₂CH(CH₃)CH₂CH₃), and the like, wherein the alkoxy group may beindependently unsubstituted or substituted with one or more substituentsdescribed in the present invention.

The term “alkylthio” refers to an alkyl group, as previously defined,attached to parent molecular moiety via a sulfur atom, i.e., alkyl-S—.In some embodiments, the alkylthio group contains 1-6 carbon atoms,i.e., C₁₋₆ alkylthio. In other embodiments, the alkylthio group contains1-4 carbon atoms, i.e., C₁₋₄ alkylthio. In other embodiments, thealkylthio group contains 1-3 carbon atoms, i.e., C₁₋₃ alkylthio. Instill other embodiment, the alkylthio group contains 1-2 carbon atoms,i.e., C₁₋₂ alkylthio. Some non-limiting examples of the alkylthio groupinclude methylthio and ethylthio, etc. The alkylthio group may beoptionally substituted with one or more substituents disclosed herein.

The term “alkylamino” refers to “N-alkylamino” and “N,N-dialkylamino”wherein the amino group is independently substituted with one alkylradical or two alkyl radicals, respectively. In some embodiments, thealkylamino group is lower alkylamino group having one or two alkylgroups of 1 to 6 carbon atoms attached to nitrogen atom. In otherembodiments, the alkylamino group is lower alkylamino group having 1 to4 carbon atoms. In other embodiments, the alkylamino group is loweralkylamino group having 1 to 3 carbon atoms. In other embodiments, thealkylamino group is lower alkylamino group having 1 to 2 carbon atoms.Some non-limiting examples of suitable alkylamino radical include monoor dialkylamino. Such examples include, but are not limited to,methylamino (N-methylamino), ethylamino (N-ethylamino), N,N-dimethylamino, N, N-diethylamino, and the like. The alkylamino groupmay be optionally substituted with one or more substituents disclosedherein.

The term “haloalkyl” refers to an alkyl group substituted with one ormore halogen atoms. In some embodiments, the haloalkyl group contains1-10 carbon atoms. In some embodiments, the haloalkyl group contains 1-8carbon atoms. In other embodiments, the haloalkyl group contains 1-6carbon atoms, i.e., C₁₋₆ haloalkyl. In other embodiments, the haloalkylgroup contains 1-4 carbon atoms, i.e., C₁₋₄ haloalkyl. In still otherembodiment, the haloalkyl group contains 1-3 carbon atoms, i.e., C₁₋₃haloalkyl. In yet other embodiment, the haloalkyl group contains 1-2carbon atoms, i.e., C₁₋₂ haloalkyl. Examples of haloalkyl include, butare not limited to, monofluoromethyl (—CH₂F), difluoromethyl (—CHF₂),trifluoromethyl (—CF₃), fluoroethyl (—CHFCH₃, —CH₂CH₂F), difluoroethyl(—CF₂CH₃, —CFHCFH₂, —CH₂CHF₂), perfluoroethyl, fluoropropyl (—CHFCH₂CH₃,—CH₂CHFCH₃, —CH₂CH₂CH₂F), difluoropropyl (—CF₂CH₂CH₃, —CFHCFHCH₃,—CH₂CH₂CHF₂, —CH₂CF₂CH₃, —CH₂CHFCH₂F), trifluoropropyl,1,1-dichloroethyl, 1,2-dichloropropyl, etc. Wherein, the haloalkyl groupmay be optionally substituted with one or more substituents disclosedherein.

The term “haloalkoxy” refers to an alkoxy group substituted with one ormore halogen atoms. In some embodiments, the haloalkoxy group contains1-10 carbon atoms. In some embodiments, the haloalkoxy group contains1-8 carbon atoms. In other embodiments, the haloalkoxy group contains1-6 carbon atoms, i.e., C₁₋₆ haloalkoxy. In other embodiments, thehaloalkoxy group contains 1-4 carbon atoms, i.e., C₁₋₄ haloalkoxy. Instill other embodiment, the haloalkoxy group contains 1-3 carbon atoms,i.e., C₁₋₆ haloalkoxy. In yet other embodiment, the haloalkoxy groupcontains 1-2 carbon atoms, i.e., C₁₋₂ haloalkoxy. Some non-limitingexamples of the haloalkoxy group include trifluoromethoxy,difluoromethoxy, etc. Wherein, the haloalkoxy group may be optionallysubstituted with one or more substituents disclosed herein.

The term “hydroxyalkyl” refers to an alkyl group substituted with one ormore hydroxy, wherein the alkyl group is as defined herein. In someembodiments, the hydroxyalkyl contains 1-6 carbon atoms, i.e., C₁₋₆hydroxyalkyl. In other embodiments, the hydroxyalkyl contains 1-4 carbonatoms, i.e., C₁₋₄ hydroxyalkyl. In other embodiments, the hydroxyalkylcontains 1-3 carbon atoms, i.e., C₁₋₃ hydroxyalkyl. In still otherembodiment, the hydroxyalkyl contains 1-2 carbon atoms, i.e., C₁₋₂hydroxyalkyl. Examples of hydroxyalkyl include, but are not limited to,hydroxymethyl, 2-hydroxyethyl (—CH₂CH₂OH), 1-hydroxyethyl (—CHOHCH₃),1,2-dihydroxyethyl (—CHOHCH₂OH), 2,3-dihydroxypropyl (—CH₂CHOHCH₂OH),1-hydroxypropyl (—CH₂CH₂CH₂OH), 2-hydroxypropyl, 3-hydroxypropyl,hydroxybutyl, etc. Wherein, the hydroxyalkyl group may be optionallysubstituted with one or more substituents disclosed herein.

The term “cycloalkyl” refers to a monocyclic, bicyclic or tricyclic ringsystem with one or more attachment points connected to the rest of themolecule, saturated, containing 3-12 ring carbon atoms. Wherein, in someembodiments, cycloalkyl is a ring system containing 3-10 ring carbonatoms; in other embodiments, cycloalkyl is a ring system containing 3-8ring carbon atoms, i.e., C₃₋₈ cycloalkyl; in other embodiments,cycloalkyl is a ring system containing 5-8 ring carbon atoms; in otherembodiments, cycloalkyl is a ring system containing 3-6 ring carbonatoms, i.e., C₃₋₆ cycloalkyl; in other embodiments, cycloalkyl is a ringsystem containing 5-6 ring carbon atoms. Examples of the cycloalkylgroup include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like. The cycloalkyl group may beoptionally substituted with one or more substituents disclosed herein.

The term “carbocyclyl” may be used alone or as a large part of“carbocyclylalkyl” or “carbocyclylalkoxy”, meaning a non-aromaticcarbocyclic system saturated or containing one or more unsaturated unitsand containing 3-14 ring carbon atoms, and does not contain any aromaticring. The term “carbocycle”, “carbocyclyl” or “carbocyclic group” isused interchangeably herein. In some embodiments, the number of ringcarbon atoms of carbocycle is 3-12; in other embodiments, the number ofring carbon atoms of carbocycle is 3-10; in other embodiments, thenumber of ring carbon atoms of carbocycle is 3-8, i.e., C₃₋₈ carbocycle(radical); in other embodiments, the number of ring carbon atoms ofcarbocycle is 3-6, i.e., C₃₋₆ carbocycle (radical); in some otherembodiments, the number of ring carbon atoms of carbocycle is 5-6; inother embodiments, the number of ring carbon atoms of carbocycle is 5-8.In other embodiments, the number of ring carbon atoms of carbocycle is6-8. This “carbocyclyl” includes monocyclic, bicyclic or polycyclicfused, spiro or bridged carbocyclic ring systems, and also includespolycyclic ring systems in which the carbocycle can be fused with one ormore non-aromatic carbocycles or one or more aromatic rings or acombination thereof, wherein the attached atomic group or point is onthe carbocycle. Bicyclic carbocyclyl includes bridged bicycliccarbocyclyl, fused bicyclic carbocyclyl and spiro bicyclic carbocyclyl.The “fused” bicyclic ring system contains two rings sharing two adjacentring atoms. Bridged bicyclic groups include two rings that share 2, 3,or 4 adjacent ring atoms. Spiro ring systems share one ring atom. Somenon-limiting examples of the carbocyclic group include cycloalkyl,cycloalkenyl and cycloalkynyl. Further examples of carbocyclyl include,but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cycloundecyl, cyclododecyl, and the like, Bridged carbocyclyl groupsinclude, but are not limited to, bicyclo [2.2.2] octyl, bicyclo [2.2.1]heptyl, bicyclo [3.3.1] nonyl, bicyclo [3.2.3] nonyl, etc. Thecarbocyclyl group can be optionally substituted with one or moresubstituents described herein.

The term “heterocyclyl” can be used alone or as a large part of“heterocyclylalkyl” or “heterocyclylalkoxy”, referring to a saturated orpartially unsaturation, nonaromatic ring having 3 to 12 ring atoms as amonocyclic, bicyclic, or tricyclic ring system, in which at least onering member is selected from nitrogen, sulfur and oxygen. Wherein, theheterocyclic group is non-aromatic and does not contain any aromaticring, and the ring system has one or more connection points connected tothe rest of the molecule. The term “heterocyclyl” includes monocyclic,bicyclic or polycyclic fused, spiro or bridged heterocyclic ringsystems. Bicyclic heterocyclic groups include bridged bicyclicheterocyclyl, fused bicyclic heterocyclyl and spiro bicyclicheterocyclyl. The terms “heterocyclyl”, “heterocyclic group” and“heterocycle” are used interchangeably herein. Unless otherwisespecified, the heterocyclyl group may be carbon or nitrogen linked, anda —CH₂— group can be optionally replaced by a —C(═O)— group. In which,the sulfur can be optionally oxygenized to S-oxide. and the nitrogen canbe optionally oxygenized to N-oxide. In some embodiments, theheterocyclyl is a ring system composed of 3-8 ring atoms; in someembodiments, the heterocyclyl is a ring system composed of 3-6 ringatoms; in some embodiments, the heterocyclyl is a ring system composedof 5-7 ring atoms; in some embodiments, the heterocyclyl is a ringsystem composed of 5-10 ring atoms; in some embodiments, theheterocyclyl is a ring system composed of 5-8 ring atoms; in otherembodiments, the heterocyclyl is a ring system composed of 6-8 ringatoms; in other embodiments, the heterocyclyl is a ring system composedof 5-6 ring atoms; in other embodiments, the heterocyclyl is a ringsystem composed of 4 ring atoms; in other embodiments, the heterocyclylis a ring system composed of 5 ring atoms; in other embodiments, theheterocyclyl is a ring system composed of 6 ring atoms; in otherembodiments, the heterocyclyl is a ring system composed of 7 ring atoms;in other embodiments, the heterocyclyl is a ring system composed of 8ring atoms.

Examples of the heterocyclyl group include, but are not limited to,oxiranyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, oxazolidine, thiazolidine, tetrahydrofuranyl,dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolanyl,dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl,homopiperidinyl, oxepanyl, thiepanyl, tetrahydropyrrolyl,dihydropyrrolyl, tetrahydropyridinyl, tetrahydropyrimidinyl,tetrahydropyrazinyl, tetrahydropyridazinyl. Some non-limiting examplesof heterocyclyl wherein —CH₂— group is replaced by —C(═O)— moietyinclude 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl,3,5-dioxopiperidinyl, pyrimidinedione-yl, and the like. Some non-limitedexamples of heterocyclyl wherein the ring sulfur atom is oxidized issulfolanyl and 1,1-dioxo-thiomorpholinyl. Bridged heterocyclyl groupsinclude, but are not limited to, 2-oxabicyclo [2.2.2] octyl,1-azabicyclo [2.2.2] octyl, 3-azabicyclo [3.2.1] octyl, etc. Theheterocyclyl group may be optionally substituted with one or moresubstituents disclosed herein.

The term “m membered”, where m is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is m. For example, piperidinyl is an example of aheterocyclic group consisting of 6 ring atoms and1,2,3,4-tetrahydronaphthyl is an example of a carbocyclic groupconsisting of 10 ring atoms.

The term “aryl” used alone or as a substantial part of “arylalkyl” or“arylalkoxy”, refers to monocyclic, bicyclic and tricyclic aromaticcarbocyclic ring systems having a total of six to fourteen ring atoms,or six to twelve ring atoms, or six to ten ring atoms, wherein each ringin the system contains 3 to 7 ring members and that has a single pointor multipoint of attachment to the rest of the molecule. The term “aryl”may be used interchangeably with the term “aryl ring” or “aromaticring”. Some non-limiting examples of the aryl group include phenyl,naphthyl and anthracene. The aryl group may be optionally substitutedwith one or more substituents disclosed herein.

The term “heteroaryl” used alone or as a major part of “heteroarylalkyl”or “heteroarylalkoxy” refers to monocyclic, bicyclic and tricyclicaromatic systems having a total of five to sixteen ring members, whereinat least one ring contains one or more heteroatoms, wherein each ringcontains 5 to 7 ring members, wherein at least one ring system isaromatic, that has a single point or multipoint of attachment to therest of the molecule. Unless otherwise stated, the heteroaryl group maybe connected to the rest of the molecule (such as the host structure inthe general formula) through any reasonable position (which may be C inCH or N in NH). When a —CH₂— group is present in the heteroaryl group,the —CH₂— group may be optionally replaced by —C(═O)—. The term“heteroaryl” and “heteroaromatic ring” or “heteroaromatic compound” canbe used interchangeably herein. In some embodiments, the heteroarylgroup is a 5-14 membered heteroaryl comprising 1, 2, 3 or 4 heteroatomsindependently selected from O, S and N. In other embodiments, theheteroaryl group is a 5-12 membered heteroaryl comprising 1, 2, 3 or 4heteroatoms independently selected from O, S and N. In otherembodiments, the heteroaryl group is a 5-10 membered heteroarylcomprising 1, 2, 3 or 4 heteroatoms independently selected from O, S andN. In other embodiments, the heteroaryl group is a 5-8 memberedheteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selectedfrom O, S and N. In other embodiments, the heteroaryl group is a 5-7membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independentlyselected from O, S and N. In other embodiments, the heteroaryl group isa 5-6 membered heteroaryl comprising 1, 2, 3 or 4 heteroatomsindependently selected from O, S and N. In other embodiments, theheteroaryl group is a 5 membered heteroaryl comprising 1, 2, 3 or 4heteroatoms independently selected from O, S and N. In otherembodiments, the heteroaryl group is a 6 membered heteroaryl comprising1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

In other embodiments, some non-limiting examples of heteroaryl include2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl,4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl,5-thiazolyl, tetrazolyl (e.g., 5H-tetrazolyl, 2H-tetrazolyl), triazolyl(e.g., 2-triazolyl, 5-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,4-triazolyl,1,2,3-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl and3-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiodiazolyl,1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, andthe following bi- or tricyclic groups: indolinyl,1,2,3,4-tetrahydroisoquinolinyl, benzimidazolyl, benzofuryl,benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g.,2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g.,1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), phenoxothiyl,dibenzimidazolyl, dibenzofuranyl, dibenzothienyl, etc. The heteroarylgroup is optionally substituted with one or more substituents disclosedherein.

The term “heteroatom” refers to one or more of oxygen, sulfur, nitrogen,phosphorus and silicon, including any oxidized form of nitrogen, sulfur,or phosphorus; the quaternized form of any basic nitrogen; or asubstitutable nitrogen of a heterocyclic ring, for example, N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as inN-substituted pyrrolidinyl, R is the substituent described in thepresent invention).

The term “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), oriodo (I).

The term “nitro” refers to —NO₂.

The term “mercapto” refers to —SH.

The term “hydroxy” refers to —OH.

The term “amino” refers to —NH₂.

The term “cyano” refers to —CN.

The term “carboxylic acid” or “carboxy” refers to —C(═O)OH.

The term “carbonyl”, whether used alone or in conjunction with otherterms, means —(C═O)—.

The term “D” refers to deuteration, i.e., ²H.

As described in the present invention, a ring system formed by drawing abond to connect a substituent to the center of the ring represents thatthe substituent can be substituted at any substitutable position on thering system. For example, formula a represents that any position on ringA that may be substituted may be optionally substituted with n R; whenring A has a bicyclic structure, R may be substituted at anysubstitutable position on any ring; for example, formula b representsthat the substituent R may be substituted at any position on the benzenering that may be substituted, as shown in formulas b-1 to b-3:

The term “protecting group” or “PG” refers to a substituent group usedto block or protect a specific functionality when other functionalgroups in the compound react. For example, an “amino-protecting group”is a substituent attached to an amino group that blocks or protects theamino functionality in the compound. Suitable amino-protecting groupsinclude acetyl, trifluoroacetyl, t-butoxy-carbonyl (BOC, Boc),benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethylenoxy-carbonyl (Fmoc).Similarly, a “hydroxy-protecting group” refers to a substituent of ahydroxy group that blocks or protects the hydroxy functionality.Suitable protecting groups include, but are not limited to, acetyl,benzoyl, benzyl, p-methoxybenzyl, silane, and the like. A“carboxy-protecting group” refers to a substituent of the carboxy groupthat blocks or protects the carboxy functionality. Commoncarboxy-protecting groups include —CH₂CH₂SO₂Ph, cyanoethyl,2-(trimethylsilyl)ethyl, 2-(trimethylsilyl) ethoxy-methyl,2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenylsulfonyl)-ethyl,2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a generaldescription of protecting groups and their use, see T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1991; and P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

The term “leaving group” or “LG” refers to an atom or functional groupthat is detached from a larger molecule in a chemical reaction, and is aterm used in nucleophilic substitution reactions and eliminationreactions. In the nucleophilic substitution reaction, the reactantattacked by the nucleophilic reagent is called a substrate, and the atomor atomic group that breaks out with a pair of electrons from thesubstrate molecule is called a leaving group. Common leaving groups are,for example, but not limited to, halogen atoms, ester groups, sulfonategroups, nitro groups, azide groups, or hydroxy.

The term “pharmaceutically acceptable” means that the substance orcomposition must be chemically and/or toxicologically compatible withthe other ingredients comprising the formulation and/or the mammal beingtreated with it. Preferably, as used herein, the term “pharmaceuticallyacceptable” means approved by a regulatory agency of the Federal or astate government or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals, and more particularly inhumans.

The term “carrier” includes any solvent, dispersion medium, coatingmaterial, surfactant, antioxidant, preservative (e.g., antibacterialagent, antifungal agent), isotonic agent, salt, drug stabilizer, binder,excipient, dispersing agent, lubricant, sweetener, flavoring agent,coloring agent, or a combination thereof, these carriers are known tothose skilled in the art (e.g., Remington's Pharmaceutical Sciences,18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except where anyconventional carrier is incompatible with the active ingredient, its usein therapeutic or pharmaceutical compositions is covered.

The term “pharmaceutical composition” refers to a mixture of one or moreof the compounds described herein, or physiologically/pharmaceuticallyacceptable salts or prodrugs thereof, and other chemical components,such as physiologically/pharmaceutically acceptable carriers,excipients, diluents, adhesives, fillers, and other additionaltherapeutic agents, such as anti-diabetic agents, antihyperglycemicagents, antiadipositas agents, antihypertensive agents, antiplateletagents, antiatherosclerotic agents, lipid-lowering agents, etc. Thepurpose of the pharmaceutical composition is to facilitateadministration of a compound to an organism.

The term “prodrug” refers to a compound that is transformed in vivo intoa compound of Formula (I). Such a transformation can be affected, forexample, by hydrolysis of the prodrug form in blood or enzymatictransformation to the parent form in blood or tissue. Prodrugs of thecompounds disclosed herein may be, for example, esters. Some commonesters which have been utilized as prodrugs are phenyl esters, aliphatic(C₁₋₂₄) esters, acyloxymethyl esters, carbonates, carbamates and aminoacid esters. For example, a compound disclosed herein that contains ahydroxy group may be acylated at this position in its prodrug form.Other prodrug forms include phosphates, such as, those phosphatecompounds derived from the phosphonation of a hydroxy group on theparent compound. A thorough discussion of prodrugs is provided inHiguchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, A.C.S.Symposium Series; Roche, et al. ed., Bioreversible Carriers in DrugDesign, American Pharmaceutical Association and Pergamon Press, 1987;Rautio et al., Prodrugs: Design and Clinical Applications, NatureReviews Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs ofPhosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345, all ofwhich are incorporated herein by reference in their entireties.

The term “metabolite” refers to a product produced through metabolism inthe body of a specified compound or salt thereof. The metabolites of acompound may be identified using routine techniques known in the art andtheir activities determined using tests such as those described herein.Such products may result for example from oxidation, reduction,hydrolysis, amidation, deamidation, esterification, deesterification,enzyme cleavage, and the like, of the administered compound.Accordingly, the invention includes metabolites of compounds disclosedherein, including metabolites produced by contacting a compounddisclosed herein with a mammal for a sufficient time period.

The term “pharmaceutically acceptable salt” refers to organic orinorganic salts of a compound disclosed herein. Pharmaceuticallyacceptable salts are well known in the art. For example, thepharmaceutically acceptable salts are described in detail in Berge etal., J. Pharmacol Sci, 1977, 66: 1-19, which is incorporated herein byreference in its entirety. Some non-limiting examples of thepharmaceutically salts include salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, metaphosphoric acid, sulfuric acid, nitric acid and perchloricacid or with organic acids such as methanesulfonic acid, ethanesulfonicacid, acetic acid, trifluoroacetic acid, glycolic acid,2-hydroxyethanesulfonic acid, oxalic acid, maleic acid, tartaric acid,citric acid, succinic acid, malonic acid, benzenesulfonic acid,p-toluenesulfonic acid, malic acid, fumaric acid, lactic acid andlactobionic acid or salts obtained by using other methods used in theart such as ion exchange. Other pharmaceutically acceptable saltsinclude adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate,lactobionate, laurate, laurylsulfate, malonate, 2-naphthalenesulfonate,nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, stearate,thiocyanate, undecanoate, valerate, and the like. Salts derived fromappropriate bases include alkali metal, alkaline earth metal, ammoniumand N⁺(C₁₋₄ alkyl)4 salts. This invention also envisions thequaternization of any basic nitrogen-containing groups of the compoundsdisclosed herein. Water or oil soluble or dispersable products may beobtained by such quaternization. Representative alkali or alkaline earthmetal salts include sodium, lithium, potassium, calcium, magnesium, andthe like. Further pharmaceutically acceptable salts include appropriateand nontoxic ammonium, quaternary ammonium, and amine cations formedusing counterions, such as halide, hydroxide, carboxylate, sulfate,phosphate, nitrate, C₁₋₈ sulfonate or aryl sulfonate.

The term “solvate” refers to an association or complex of one or moresolvent molecules and a compound disclosed herein. Some non-limitingexamples of the solvent that form solvates include water, isopropanol,ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acidand ethanolamine. The term “hydrate” refers to the complex where thesolvent molecule is water.

The term “N-oxide” refers to one or more than one nitrogen atomsoxidised to form an N-oxide, where a compound contains several aminefunctions. Particular examples of N-oxides are the N-oxides of atertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.N-oxides can be formed by treatment of the corresponding amine with anoxidizing agent such as hydrogen peroxide or a per-acid (e.g., aperoxycarboxylic acid) (See, Advanced Organic Chemistry, by Jerry March,4th Edition, Wiley Interscience, pages). More particularly, N-oxides canbe made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) inwhich the amine compound is reacted with m-chloroperoxybenzoic acid(m-CPBA), for example, in an inert solvent such as dichloromethane.

Any asymmetric atom (e.g., carbon or the like) of the compound(s)disclosed herein can be present in racemic or enantiomerically enriched,for example the (R)-, (S)-, (R, S)- or (S, S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. If possible, the substituent on the atomhaving an unsaturated double bond may exist in the form of -(Z)- or-(E)-.

Therefore, as described in the present invention, the compound of thepresent invention may exist in one form or a mixture of possibleisomers, rotamers, atropisomers, tautomers, e.g., in the form ofsubstantially pure geometric (cis or trans) isomers, diastereomers,optical isomers (enantiomers), racemates or mixtures thereof.

Any resulting mixtures of stereoisomers can be separated on the basis ofthe physicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by methods known to those skilled inthe art, e.g., by separation of the diastereomeric salts thereof.Racemic products can also be resolved by chiral chromatography, e.g.,high performance liquid chromatography (HPLC) using a chiral adsorbent.Preferred enantiomers can also be prepared by asymmetric syntheses. See,for example, Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis(2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, U K, 2012);Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, N Y,1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutionsp. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind.1972);

The present invention also includes isotopically labeled compounds ofthe present invention, which are the same as those described in thepresent invention except for the fact that one or more atoms arereplaced by atoms having an atomic mass or mass number different fromthe atomic mass or mass number common in nature. Examples of isotopesthat can be incorporated into compounds of the invention includeisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur,fluorine, and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁶O, ¹⁷O, ³¹P,³²P, ³⁶S, ¹⁸F and ³⁷Cl.

Compounds of the invention containing the aforementioned isotopes and/orother isotopes of other atoms and pharmaceutically acceptable salts ofthe compounds are included within the scope of the invention.Isotopically-labeled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H or ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Due to ease of preparation and detection, tritiated, i.e., ³H,and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred. Inaddition, substitution with heavy isotopes, such as deuterium, i.e., ²H,may provide some therapeutic advantages derived from greater metabolicstability, such as increased half-life in the body or reduced dosagerequirements. Therefore, it may be preferable in some cases.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds disclosed herein may contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds disclosedherein, including, but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand 1 or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or 1 meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that these stereoisomers are mirror images of eachother. A specific stereoisomer is referred to as an enantiomer, and amixture of such isomers is often called an enantiomeric mixture. A 50:50mixture of enantiomers is referred to as a racemic mixture or aracemate, which may occur where there has been no stereoselection orstereospecificity in a chemical reaction or process.

Depending on the choice of the starting materials and procedures, thecompounds can be present in the form of one of the possiblestereoisomers or as mixtures thereof, such as pure optical isomers, oras a mixture of isomers, or as racemates and diastereoisomer mixtures,depending on the number of asymmetric carbon atoms. Optically active(R)- and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. If the compoundcontains a double bond, the substituent may be E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans-configuration.

The compounds disclosed herein may contain asymmetric or chiral centers,and therefore exist in different stereoisomeric forms. It is expectedthat all stereoisomeric forms of the compounds of the invention,including but not limited to diastereomers, enantiomers, atropisomers,geometric (or conformational) isomers and their mixtures, such asracemic mixtures, are within the scope of the present invention.

Unless otherwise indicated, the structures described in the presentinvention also include all isomers (e.g., enantiomers, diastereomers,atropisomers, and geometric (or conformational)) forms including thisstructure; for example, the R and S configurations of each asymmetriccenter, (Z) and (E) double bond isomers, and (Z) and (E) conformationalisomers. Therefore, single stereochemical isomers of the compounds ofthe present invention as well as mixtures of enantiomers, diastereomersand mixtures of geometric isomers (or conformers) are within the scopeof the present invention.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.Where tautomerization is possible (e.g. in solution), a chemicalequilibrium of tautomers can be reached. For example, protontautomers(also known as prototropic tautomers) include interconversions viamigration of a proton, such as keto-enol and imine-enamineisomerizations. Valence tautomers include interconversions byreorganization of some of the bonding electrons. A specific example ofketo-enol tautomerization is the interconversion of pentane-2,4-dioneand 4-hydroxypent-3-en-2-one tautomers. Another example oftautomerization is phenol-keto tautomerization. The specific example ofphenol-keto tautomerisms is pyridin-4-ol and pyridin-4(1H)-onetautomerism. Unless otherwise stated, all tautomeric forms of thecompounds disclosed herein are within the scope of the invention.

The term “geometric isomers” also called “cis-trans isomers” refers toisomers caused by double bonds (including double bonds of olefins, C═Ndouble bonds and N═N double bonds) or single bonds of ring carbon atomsthat cannot rotate freely.

The term “dimer” refers to substances of the same or the same kind,appearing in a double form, and may have properties or functions thatare not available in a single state. Common examples includedicyclopentadiene, cuprous dichloride, sucrose, and so on.

The term “trimer” refers to three substances of the same or the samekind that are polymerized into a new molecule. The new molecule is atrimer and is a low molecular weight polymer.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice, fish, birds and the like. In certain embodiments, the subject is aprimate. In yet other embodiments, the subject is a human.

As used herein, the terms “subject” and “patient” are usedinterchangeably. The terms “subject” and “patient” refer to animals(e.g., birds or mammals such as chickens, quails, or turkeys),especially “mammals” including non-primates (e.g., cattle, pigs, horses,sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates(e.g., monkeys, chimpanzees, and humans), and more particularly humans.In one embodiment, the subject is a non-human animal, such as a domesticanimal (e.g., horse, cow, pig, or sheep) or a pet (e.g., dog, cat,guinea pig, or rabbit). In other embodiments, “patient” refers to ahuman.

The term “syndrome X”, also known as conditions, diseases of metabolicsyndrome, the disorders are detailed in Johannsson et al., J. Clin.Endocrinol. Metab., 1997; 82, 727-734, which is incorporated herein byreference.

The term “intestinal improvement” refers to increasing beneficialbacteria such as Bifidobacterium, Lactobacillus, etc., increasingorganic acids in the intestine, and reducing spoilage products in theintestine.

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byunregulated cell growth. A “tumor” comprises one or more cancerouscells. Examples of cancer include, but are not limited to, carcinoma,lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. Moreparticular examples of such cancers include squamous cell cancer (e.g.,epithelial squamous cell cancer), lung cancer including small-cell lungcancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lungand squamous carcinoma of the lung, cancer of the peritoneum,hepatocellular cancer, gastric or stomach cancer includinggastrointestinal cancer, pancreatic cancer, glioblastoma, cervicalcancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breastcancer, colon cancer, rectal cancer, colorectal cancer, endometrial oruterine carcinoma, salivary gland carcinoma, kidney or renal cancer,prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, analcarcinoma, penile carcinoma, as well as head and neck cancer.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the onset or development or progression of the disease ordisorder.

DESCRIPTION OF COMPOUNDS OF THE INVENTION

The present invention provides a compound with excellent SGLTsinhibitory activity, especially compound with excellent SGLT1 inhibitoryactivity, used for the preparation of drugs for improving the intestinalenvironment; or for the preparation of drugs for treating diabetes,diabetes complications, insulin resistance, hyperglycemia,hyperinsulinemia, hyperlipidemia, obesity, syndrome X, atherosclerosis,cardiovascular disease, congestive heart failure, hypomagnesemia,hyponatremia, renal failure, disorders related to blood concentration,constipation, or high blood pressure. The present invention alsoprovides methods of preparing these compounds, pharmaceuticalcompositions comprising these compounds, and methods of using thesecompounds and compositions to prepare medicaments for theabove-mentioned diseases in mammals, especially humans. Compared withthe existing similar compounds, the compounds of the present inventionnot only have better pharmacological activity, but also have better invivo metabolic kinetic properties and in vivo pharmacodynamicproperties. At the same time, the preparation method is simple and easy,and the technological method is stable, which is suitable for industrialproduction. Therefore, the compound provided by the present inventionhas better druggability compared with the existing similar compounds.

Specifically:

in one aspect, the invention relates to a compound having Formula (I) ora stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, ametabolite, a pharmaceutically acceptable salt, a dimer, a trimer or aprodrug thereof,

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, L, n and t have thedefinition as described in the present invention, with the proviso thatwhen R⁵ and R⁸ are both H and R⁹ is

t is not 0.

In some embodiments, L is —(CR^(a)R^(b))_(q)—,—CH═CH—(CR^(a)R^(b))_(p)—, —O—(CR^(a)R^(b))_(p)—,—NH—(CR^(a)R^(b))_(p)—, —S—(CR^(a)R^(b))_(p)—, —S(═O)—(CR^(a)R^(b))_(p)—or —S(═O)₂—(CR^(a)R^(b))_(p)—;

q is 1, 2, 3, 4, 5 or 6;

p is 0, 1, 2, 3, 4, 5 or 6;

each R^(a) and R^(b) is independently H, D, F, Cl, Br, I, CN, NO₂, OH,NH₂, —C(═O) OH, —SH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ haloalkoxy, C₃₋₆cycloalkyl or 3-6 membered heterocyclyl; or, R^(a) and R^(b) togetherwith the carbon atom to which they are attached, form a C₃₋₆ carbocycleor a 3-6 membered heterocycle;

R¹ is H, D, F, Cl, Br, I, OH, CN, NO₂, NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylthio, C₃₋₆ cycloalkyl or C₃₋₆cycloalkyl-C₁₋₄ alkylene, wherein each of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylthio, C₃₋₆ cycloalkyl and C₃₋₆cycloalkyl-C₁₋₄ alkylene is independently unsubstituted or substitutedwith 1, 2, 3 or 4 substituents, and the substituent is independentlyselected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino or C₁₋₆ haloalkoxy;

each of R² and R³ is independently H, D, CN, OH, NH₂, —SH, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆alkylamino, C₃₋₆ cycloalkyl or 3-6 membered heterocyclyl, wherein eachC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio,C₁₋₆ alkylamino, C₃₋₆ cycloalkyl and 3-6 membered heterocyclyl isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, ═O, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino or C₁₋₆ haloalkoxy;

or, R² and R³ together with the carbon atom to which they are attached,form carbonyl, or, R² and R³ together with the carbon atom to which theyare attached, form a C₃₋₆ carbocycle or a 3-6 membered heterocycle,wherein each of C₃₋₆ carbocycle and 3-6 membered heterocycle isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, ═O, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino or C₁₋₆ haloalkoxy;

R⁴ is H, D, —OR^(4a) or —SR^(4b);

each of R^(4a) and R^(4b) is independently H, D, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, 5-6 membered heterocyclyl,(5-6 membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkylene, 5-6 membered heteroaryl or (5-6 membered heteroaryl)-C₁₋₄alkylene, wherein each C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄alkylene, 5-6 membered heterocyclyl, (5-6 membered heterocyclyl)-C₁₋₄alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5-6 membered heteroaryland (5-6 membered heteroaryl)-C₁₋₄ alkylene is independentlyunsubstituted or substituted with 1, 2, 3 or 4 substituents, and thesubstituent is independently selected from D, F, Cl, Br, I, CN, NO₂, OH,NH₂, —C(═O) OH, —SH, ═O, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆alkylamino or C₁₋₆ haloalkoxy;

R¹⁰ is H, D, F, Cl, Br, I, OH, CN, NO₂, NH₂, C₁₋₆ alkyl or C₁₋₆ alkoxy;

R⁵ is H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, 3-8 memberedheterocyclyl, C₆₋₁₀ aryl or 5-8 membered heteroaryl, wherein each ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl,C₆₋₁₀ aryl and 5-8 membered heteroaryl is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O,—C(═O) OH, —C(═O) NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ haloalkoxy, C₃₋₆cycloalkyl, 5-6 membered heterocyclyl, C₆₋₁₀ aryl or 5-6 memberedheteroaryl;

each of R⁶ and R⁷ is H, D, F, Cl, Br, I, CN, NO₂, OH, NH₂, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₈cycloalkyl, 3-8 membered heterocyclyl, C₆₋₁₀ aryl or 5-8 memberedheteroaryl, wherein each C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl,C₆₋₁₀ aryl and 5-8 membered heteroaryl is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O,—C(═O) OH, —C(═O) NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ haloalkoxy, C₃₋₆cycloalkyl, 5-6 membered heterocyclyl, C₆₋₁₀ aryl or 5-6 memberedheteroaryl;

or, R⁶ and R⁷ together with the carbon atom to which they are attached,form a C₃₋₈ carbocycle, a 3-8 membered heterocycle, a C₆₋₁₀ aromaticring or a 5-8 membered heteroaromatic ring, wherein each of C₃₋₈carbocycle, 3-8 membered heterocycle, C₆₋₁₀ aromatic ring and 5-8membered heteroaromatic ring is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O,—C(═O) OH, —C(═O) NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino or C₁₋₆ haloalkoxy;

or R⁵ and R⁶ together with the atom to which they are attached, or R⁵and R⁷ together with the atom to which they are attached, form a 3-8membered heterocycle or a 5-8 membered heteroaromatic ring, wherein each3-8 membered heterocycle and 5-8 membered heteroaromatic ring isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, ═O, —C(═O) OH, —C(═O) NH₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino orC₁₋₆ haloalkoxy;

each of R⁸ and R⁹ is independently H, D, R^(e)O—C₁₋₄ alkylene,R^(d)R^(c)N—C₁₋₄ alkylene, C₁₋₈ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl,C₃₋₈ cycloalkyl-C₁₋₄ alkylene, 3-8 membered heterocyclyl, (3-8 memberedheterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5-8membered heteroaryl or (5-8 membered heteroaryl)-C₁₋₄ alkylene, whereineach C₁₋₈ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₄alkylene, 3-8 membered heterocyclyl, (3-8 membered heterocyclyl)-C₁₋₄alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5-8 membered heteroaryland (5-8 membered heteroaryl)-C₁₋₄ alkylene is independentlyunsubstituted or substituted with 1, 2, 3 or 4 substituents, and thesubstituent is independently selected from D, F, Cl, Br, I, CN, NO₂, ═O,—OR^(e), —NR^(c)R^(d), —C(═O)OR^(e), —C(═O) NHR^(f), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino orC₁₋₆ haloalkoxy;

or, R⁸ and R⁹ together with the nitrogen atom to which they areattached, form a 3-8 membered heterocycle or a 5-8 memberedheteroaromatic ring, wherein each of 3-8 membered heterocycle and 5-8membered heteroaromatic ring is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, ═O, —OR^(e),—NR^(c)R^(d), —C(═O)OR^(e), —C(═O)NHR^(f), C₁₋₆ alkyl, C₂₋₆ alkenyl,C²⁻⁶ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino or C₁₋₆haloalkoxy;

each R^(c), R^(d), R^(e) and R^(f) is independently H, D, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkyl-C₁₋₄ alkylene, 3-8membered heterocyclyl, (3-8 membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5-8 membered heteroaryl or (5-8 memberedheteroaryl)-C₁₋₄ alkylene, wherein each C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₄ alkylene, 3-8 membered heterocyclyl,(3-8 membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkylene, 5-8 membered heteroaryl and (5-8 membered heteroaryl)-C₁₋₄alkylene is independently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, —NH₂, ═O, —C(═O)OH, —C(═O)NH₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino orC₁₋₆ haloalkoxy;

or, R^(c) and R^(d) together with the nitrogen atom to which they areattached, form a 3-8 membered heterocycle or a 5-8 memberedheteroaromatic ring, wherein each of 3-8 membered heterocycle and 5-8membered heteroaromatic ring is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, ═O, OH, —NH₂,—C(═O)OH, —C(═O)NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C²⁻⁶ alkynyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino or C₁₋₆ haloalkoxy;

n is 0, 1, 2 or 3;

-   -   t is 0, 1, 2, 3, 4, 5 or 6; with the proviso that when R⁵ and R⁸        are both H and R⁹ is

is not 0.

In other embodiments, the present invention relates to a compound havingformula (I-a) or a stereoisomer, a geometric isomer, a tautomer, anN-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, adimer, a trimer or a prodrug thereof,

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, L n and t are asdefined herein.

In other embodiments, the present invention relates to a compound havingformula (II), or a stereoisomer, a geometric isomer, a tautomer, anN-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, adimer, a trimer or a prodrug thereof,

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, n and t are as definedherein.

In other embodiments, R¹ is H, D, F, Cl, Br, I, OH, CN, NO₂, NH₂, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄ hydroxyalkyl, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ alkylamino, C₁₋₄ alkylthio, C₃₋₆cycloalkyl or C₃₋₆ cycloalkyl-C₁₋₂ alkylene, wherein each of C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄ hydroxyalkyl, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ alkylamino, C₁₋₄ alkylthio, C₃₋₆cycloalkyl and C₃₋₆ cycloalkyl-C₁₋₂ alkylene is independentlyunsubstituted or substituted with 1, 2, 3 or 4 substituents, and thesubstituent is independently selected from D, F, Cl, Br, I, CN, NO₂, OH,NH₂, —C(═O) OH, —SH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄alkylamino or C₁₋₄ haloalkoxy.

In still other embodiments, R¹ is H, D, F, Cl, Br, I, OH, CN, NO₂, NH₂,methyl, ethyl, n-propyl, isopropyl, propenyl, propynyl, methoxy, ethoxy,hydroxymethyl, trifluoromethyl, trifluoroethyl, monofluoromethyl,trifluoromethoxy, difluoromethoxy, methylamino, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cyclopropyl-methylene, wherein each ofmethyl, ethyl, n-propyl, isopropyl, propenyl, propynyl, methoxy, ethoxy,hydroxymethyl, trifluoroethyl, monofluoromethyl, difluoromethoxy,methylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcyclopropyl-methylene is independently unsubstituted or substituted with1, 2, 3, or 4 substituents, and the substituent is independentlyselected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, methyl,ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy,methylamino, trifluoromethoxy or difluoromethoxy.

In other embodiments, each of R² and R³ is independently H, D, CN, OH,NH₂, —SH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ alkylamino, C₃₋₆ cycloalkyl or 5-6 memberedheterocyclyl, wherein each C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, C₃₋₆ cycloalkyl and 5-6membered heterocyclyl is independently unsubstituted or substituted with1, 2, 3 or 4 substituents, and the substituent is independently selectedfrom D, F, Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, ═O, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino or C₁₋₄ haloalkoxy.

In still other embodiments, each of R² and R³ is independently H, D, CN,OH, NH₂, —SH, methyl, ethyl, n-propyl, isopropyl, vinyl, propynyl,methoxy, ethoxy, methylthio, methylamino, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or 5-6 membered heterocyclyl, wherein eachmethyl, ethyl, n-propyl, isopropyl, vinyl, propynyl, methoxy, ethoxy,methylthio, methylamino, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and 5-6 membered heterocyclyl is independently unsubstitutedor substituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O)OH, —SH, ═O, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl,methoxy, ethyloxy, methylamino, trifluoromethoxy or difluoromethoxy.

In other embodiments, R² and R³ together with the carbon atom to whichthey are attached, form carbonyl.

In other embodiments, R² and R³ together with the carbon atom to whichthey are attached, form a C₃₋₆ carbocycle or a 5-6 membered heterocycle,wherein each of C₃₋₆ carbocycle and 5-6 membered heterocycle isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, ═O, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino or C₁₋₄ haloalkoxy.

In still other embodiments, R² and R³ together with the carbon atom towhich they are attached, form cyclopropane, cyclobutane, cyclopentane,cyclohexane or a 5-6 membered heterocycle, wherein each of cyclopropane,cyclobutane, cyclopentane, cyclohexane and a 5-6 membered heterocycle isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, ═O, methyl, ethyl,n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, methylamino,trifluoromethoxy or difluoromethoxy.

In other embodiments, R⁴ is H, D, —OR^(4a) or —SR^(4b);

each of R^(4a) and R^(4b) is independently H, D, C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene, 5-6 membered heterocyclyl,(5-6 membered heterocyclyl)-C₁₋₂ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₂alkylene, 5-6 membered heteroaryl or (5-6 membered heteroaryl)-C₁₋₂alkylene, wherein each C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂alkylene, 5-6 membered heterocyclyl, (5-6 membered heterocyclyl)-C₁₋₂alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₂ alkylene, 5-6 membered heteroaryland (5-6 membered heteroaryl)-C₁₋₂ alkylene is independentlyunsubstituted or substituted with 1, 2, 3 or 4 substituents, and thesubstituent is independently selected from D, F, Cl, Br, I, CN, NO₂, OH,NH₂, —C(═O) OH, —SH, ═O, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄alkylamino or C₁₋₄ haloalkoxy.

In still other embodiments, R⁴ is H, D, —OR^(4a) or —SR^(4b);

each of R^(4a) and R^(4b) is independently H, D, methyl, ethyl,n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,C₃₋₆ cycloalkyl-C₁₋₂ alkylene, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, (5-6 membered heterocyclyl)-C₁₋₂ alkylene, phenyl,phenyl-C₁₋₂ alkylene, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinylor (5-6 membered heteroaryl)-C₁₋₂ alkylene, wherein each methyl, ethyl,n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,C₃₋₆ cycloalkyl-C₁₋₂ alkylene, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, (5-6 membered heterocyclyl)-C₁₋₂ alkylene, phenyl,phenyl-C₁₋₂ alkylene, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyland (5-6 membered heteroaryl)-C₁₋₂ alkylene is independentlyunsubstituted or substituted with 1, 2, 3, or 4 substituents, and thesubstituent is independently selected from D, F, Cl, Br, I, CN, NO₂, OH,NH₂, —C(═O) OH, —SH, ═O, methyl, ethyl, n-propyl, isopropyl,trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxy ordifluoromethoxy.

In other embodiments, R¹⁰ is H, D, F, Cl, Br, I, OH, CN, NO₂, NH₂, C₁₋₄alkyl or C₁₋₄ alkoxy.

In still other embodiments, R¹⁰ is H, D, F, Cl, Br, I, OH, CN, NO₂, NH₂,methyl, ethyl, n-propyl, isopropyl, methoxy or ethoxy.

In other embodiments, R⁵ is H, D, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl, 5-6 membered heterocyclyl, C₆₋₁₀ aryl or 5-6 memberedheteroaryl, wherein each of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl,5-6 membered heterocyclyl, C₆₋₁₀ aryl and 5-6 membered heteroaryl isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, ═O, —C(═O) OH, —C(═O) NH₂, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, 5-6 membered heterocyclyl, C₆₋₁₀ arylor 5-6 membered heteroaryl.

In still other embodiments, R⁵ is H, D, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl,piperidinyl, morpholinyl, thiomorpholyl, piperazinyl, phenyl, furyl,pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl,pyridazinyl or pyrimidinyl, wherein each of methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl,piperidinyl, morpholinyl, thiomorpholyl, piperazinyl, phenyl, furyl,pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl,pyridazinyl and pyrimidinyl is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O,—C(═O) OH, —C(═O) NH₂, methyl, ethyl, n-propyl, isopropyl, vinyl,ethynyl, trifluoromethyl, methoxy, ethoxy, methylamino,trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentylor phenyl.

In other embodiments, each of R⁶ and R⁷ is independently H, D, F, Cl,Br, I, CN, NO₂, OH, NH₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, 5-6 membered heterocyclyl,C₆₋₁₀ aryl or 5-6 membered heteroaryl, wherein each C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ alkylamino, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆cycloalkyl, 5-6 membered heterocyclyl, C₆₋₁₀ aryl and 5-6 memberedheteroaryl is independently unsubstituted or substituted with 1, 2, 3 or4 substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, ═O, —C(═O) OH, —C(═O) NH₂, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, 5-6 membered heterocyclyl, C₆₋₁₀ arylor 5-6 membered heteroaryl.

In still other embodiments, each of R⁶ and R⁷ is independently H, D, F,Cl, Br, I, CN, NO₂, OH, NH₂, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, methylamino,trifluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl,piperidinyl, morpholinyl, thiomorpholyl, piperazinyl, phenyl, furyl,pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl,pyridazinyl or pyrimidinyl, wherein each methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, methylamino,difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl,1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl andpyrimidinyl is independently unsubstituted or substituted with 1, 2, 3or 4 substituents, and the substituent is independently selected from D,F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O, —C(═O) OH, —C(═O) NH₂, methyl,ethyl, n-propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, methoxy,ethoxy, methylamino, trifluoromethoxy, difluoromethoxy, cyclopropyl,cyclobutyl, cyclopentyl or phenyl.

In other embodiments, R⁶ and R⁷ together with the carbon atom to whichthey are attached, form a C₃₋₆ carbocycle, a 5-6 membered heterocycle, aC₆₋₁₀ aromatic ring or a 5-6 membered heteroaromatic ring, wherein eachof C₃₋₆ carbocycle, 5-6 membered heterocycle, C₆₋₁₀ aromatic ring and5-6 membered heteroaromatic ring is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O,—C(═O) OH, —C(═O) NH₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino or C₁₋₄ haloalkoxy.

In still other embodiments, R⁶ and R⁷ together with the carbon atom towhich they are attached, form cyclopropane, cyclobutane, cyclopentane,cyclohexane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene,tetrahydropyran, tetrahydrothiopyran, piperidine, morpholine,thiomorpholine, piperazine, benzene ring, furan, pyrrole, pyridine,pyrazole, imidazole, triazole, tetrazole, oxazole, oxadiazole,1,3,5-triazine, thiazole, thiophene, pyrazine, pyridazine or pyrimidine,wherein each of cyclopropane, cyclobutane, cyclopentane, cyclohexane,pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran,tetrahydrothiopyran, piperidine, morpholine, thiomorpholine, piperazine,benzene ring, furan, pyrrole, pyridine, pyrazole, imidazole, triazole,tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole, thiophene,pyrazine, pyridazine and pyrimidine is independently unsubstituted orsubstituted with 1, 2, 3, or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O,—C(═O) OH, —C(═O) NH₂, methyl, ethyl, n-propyl, isopropyl, vinyl,ethynyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxyor difluoromethoxy.

In other embodiments, R⁵ and R⁶ together with the atom to which they areattached, or R⁵ and R⁷ together with the atom to which they areattached, form a 3-6 membered heterocycle or a 5-6 memberedheteroaromatic ring, wherein each 3-6 membered heterocycle and 5-6membered heteroaromatic ring is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O,—C(═O) OH, —C(═O) NH₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino or C₁₋₄ haloalkoxy.

In still other embodiments, R⁵ and R⁶ together with the atom to whichthey are attached, or R⁵ and R⁷ together with the atom to which they areattached, form aziridine, azetidine, pyrrolidine, pyrazolidine,imidazolidine, oxazolidine, thiazolidine, piperidine, morpholine,thiomorpholine, piperazine, pyrrole, pyridine, pyrazole, imidazole,triazole, tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole,pyrazine, pyridazine or pyrimidine, wherein each aziridine, azetidine,pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, thiazolidine,piperidine, morpholine, thiomorpholine, piperazine, pyrrole, pyridine,pyrazole, imidazole, triazole, tetrazole, oxazole, oxadiazole,1,3,5-triazine, thiazole, pyrazine, pyridazine and pyrimidine isindependently unsubstituted or substituted with 1, 2, 3, or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, ═O, —C(═O) OH, —C(═O) NH₂, methyl, ethyl,n-propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, methoxy, ethoxy,methylamino, trifluoromethoxy or difluoromethoxy.

In other embodiments, each of R⁸ and R⁹ is independently H, D,R^(e)O—C₁₋₄ alkylene, R^(d)R^(c)N—C₁₋₄ alkylene, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene, 5-6 memberedheterocyclyl, (5-6 membered heterocyclyl)-C₁₋₂ alkylene, C₆₋₁₀ aryl,C₆₋₁₀ aryl-C₁₋₂ alkylene, 5-6 membered heteroaryl or (5-6 memberedheteroaryl)-C₁₋₂ alkylene, wherein each C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene, 5-6 membered heterocyclyl,(5-6 membered heterocyclyl)-C₁₋₂ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₂alkylene, 5-6 membered heteroaryl and (5-6 membered heteroaryl)-C₁₋₂alkylene is independently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, ═O, —OR^(e), —NR^(c)R^(d), —C(═O)OR^(e), —C(═O)NHR^(f), C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ alkylamino or C₁₋₄ haloalkoxy.

In still other embodiments, each of R⁸ and R⁹ is independently H, D,R^(d)R^(c)N—C₁₋₄ alkylene, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl, n-hexyl, trifluoromethyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene,pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,thiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, (5-6 membered heterocyclyl)-C₁₋₂ alkylene, phenyl, C₆₋₁₀aryl-C₁₋₂ alkylene, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl,thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl or (5-6 memberedheteroaryl)-C₁₋₂ alkylene, wherein each methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C₃₋₆ cycloalkyl-C₁₋₂alkylene, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,thiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, (5-6 membered heterocyclyl)-C₁₋₂ alkylene, phenyl, C₆₋₁₀aryl-C₁₋₂ alkylene, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl,thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl and (5-6membered heteroaryl)-C₁₋₂ alkylene is independently unsubstituted orsubstituted with 1, 2, 3, or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, ═O, —OH,—NR^(c)R^(d), —C(═O)OH, —C(═O)NH₂, methyl, ethyl, n-propyl, vinyl,ethynyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxyor difluoromethoxy.

In other embodiments, R⁸ and R⁹ together with the nitrogen atom to whichthey are attached, form a 3-6 membered heterocycle or a 5-6 memberedheteroaromatic ring, wherein each of 3-6 membered heterocycle and 5-6membered heteroaromatic ring is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, ═O, —OR^(e),—NR^(c)R^(d), —C(═O)OR^(e), —C(═O)NHR^(f), C₁₋₄ alkyl, C₂₋₄ alkenyl,C²⁻⁴ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino or C₁₋₄haloalkoxy.

In still other embodiments, R⁸ and R⁹ together with the nitrogen atom towhich they are attached, form aziridine, azetidine, pyrrolidine,pyrazolidine, imidazolidine, oxazolidine, thiazolidine, piperidine,morpholine, thiomorpholine, piperazine, pyrazole, imidazole, triazole,tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole, pyrazine,pyridazine or pyrimidine, wherein each of aziridine, azetidine,pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, thiazolidine,piperidine, morpholine, thiomorpholine, piperazine, pyrazole, imidazole,triazole, tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole,pyrazine, pyridazine and pyrimidine is independently unsubstituted orsubstituted with 1, 2, 3, or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, ═O, —OH,—NR^(c)R^(d), —C(═O) OH, —C(═O) NH₂, methyl, ethyl, n-propyl, vinyl,ethynyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxyor difluoromethoxy.

In other embodiments, each R^(c), R^(d), R^(e) and R^(f) isindependently H, D, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, 5-6 membered heterocyclyl, (5-6 memberedheterocyclyl)-C₁₋₂ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₂ alkylene, 5-6membered heteroaryl or (5-6 membered heteroaryl)-C₁₋₂ alkylene, whereineach C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂alkylene, 5-6 membered heterocyclyl, (5-6 membered heterocyclyl)-C₁₋₂alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₂ alkylene, 5-6 membered heteroaryland (5-6 membered heteroaryl)-C₁₋₂ alkylene is independentlyunsubstituted or substituted with 1, 2, 3 or 4 substituents, and thesubstituent is independently selected from D, F, Cl, Br, I, CN, NO₂, OH,—NH₂, ═O, —C(═O)OH, —C(═O)NH₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino or C₁₋₄ haloalkoxy.

In still other embodiments, each R^(c), R^(d), R^(e) and R^(f) isindependently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene, pyrrolidinyl,pyrazolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, (5-6 membered heterocyclyl)-C₁₋₂ alkylene, phenyl,phenyl-C₁₋₂ alkylene, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl,thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl or (5-6 memberedheteroaryl)-C₁₋₂ alkylene, wherein each methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene, pyrrolidinyl,pyrazolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, (5-6 membered heterocyclyl)-C₁₋₂ alkylene, phenyl,phenyl-C₁₋₂ alkylene, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl,thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl and (5-6membered heteroaryl)-C₁₋₂ alkylene is independently unsubstituted orsubstituted with 1, 2, 3, or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, —NH₂, ═O,—C(═O) OH, —C(═O) NH₂, methyl, ethyl, n-propyl, isopropyl, vinyl,ethynyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxyor difluoromethoxy.

In other embodiments, R^(c) and R^(d) together with the nitrogen atom towhich they are attached, form a 3-6 membered heterocycle or a 5-6membered heteroaromatic ring, wherein each of 3-6 membered heterocycleand 5-6 membered heteroaromatic ring is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, ═O, OH, —NH₂,—C(═O)OH, —C(═O)NH₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C²⁻⁴ alkynyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino or C₁₋₄ haloalkoxy.

In still other embodiments, R^(c) and R^(d) together with the nitrogenatom to which they are attached, form aziridine, azetidine, pyrrolidine,pyrazolidine, imidazolidine, oxazolidine, thiazolidine, piperidine,morpholine, thiomorpholine, piperazine, pyrazole, imidazole, triazole,tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole, pyrazine,pyridazine or pyrimidine, wherein each of aziridine, azetidine,pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, thiazolidine,piperidine, morpholine, thiomorpholine, piperazine, pyrazole, imidazole,triazole, tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole,pyrazine, pyridazine and pyrimidine is independently unsubstituted orsubstituted with 1, 2, 3, or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O,—C(═O) OH, —C(═O) NH₂, methyl, ethyl, n-propyl, isopropyl, vinyl,ethynyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxyor difluoromethoxy.

In some embodiments, the present invention relates to one of thefollowing structures, or a stereoisomer, geometric isomers, a tautomer,an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt,a dimer, a trimer or a prodrug thereof,

In other aspect, provided herein is a pharmaceutical compositioncomprising the compound disclosed herein.

In some embodiments, the pharmaceutical composition of the presentinvention further comprises a pharmaceutically acceptable carrier,excipient, adjuvant, vehicle or a combination thereof.

In some embodiments, the pharmaceutical composition of the presentinvention further comprises one or more other additional therapeuticagents, wherein the other additional therapeutic agent is selected froman anti-diabetic drug, an anti-hyperglycemic drug, an anti-obesity drug,an anti-hypertensive drug, an appetite suppressant drug, alipid-lowering drug, or a combination thereof.

In some embodiments, the pharmaceutical composition of the presentinvention can be in the form of a liquid, solid, semi-solid, gel orspray.

In other embodiments, each anti-diabetic and anti-hyperglycemic drug ofthe present invention is independently selected from a SGLT2 inhibitor,a biguanide drug, a sulfonylurea drug, a glucosidase inhibitor, a PPARagonist (peroxisome proliferator-activated receptor agonist), a αP2inhibitor (fat cell fatty acid binding protein inhibitor), a PPARα/γdual activator (peroxisome proliferator-activated receptor α/γ dualactivator), a dipeptidyl peptidase IV inhibitor, a glinides drug, aninsulin, a glucagon-like peptide-1 inhibitor, a PTP1B inhibitor (proteintyrosine phosphatase 1B inhibitor), a glycogen phosphorylase inhibitor,a glucose-6-phosphatase inhibitor or a combination thereof.

In other embodiments, the anti-obesity drug of the present invention isselected from a central anti-obesity drug, a MCH (black pigmentconcentrating hormone) receptor antagonist, a neuropeptide Y receptorantagonist, a cannabinoid receptor antagonist, a cerebrointestinalpeptide antagonist, a lipase inhibitor, a β3 agonist, a 11β-HSD1 (11βhydroxysteroid dehydrogenase 1) inhibitor, a DGAT-1 (diacylglycerolacyltransferase 1) inhibitor, a peptide appetite inhibitor, acholecystokinin agonist, a feeding inhibitor or a combination thereof.

In other embodiments, the antihypertensive drug of the present inventionis selected from an angiotensin converting enzyme inhibitor, anangiotensin II receptor antagonist, a calcium channel antagonist, apotassium channel opener, a diuretic, or a combination thereof.

In other embodiments, the lipid-lowering drug of the present inventionis selected from a MTP inhibitor (microsomal triglyceride transferprotein inhibitor), a HMGCoA reductase inhibitor (hydroxymethylglutarylcoenzyme A reductase inhibitor), a squalene synthase inhibitor, abetinic acid-type hypolipidemic drug (also known as fibratehypolipidemic drug), an ACAT inhibitor (acetylcholesterolacetyltransferase inhibitor), a lipoxygenase inhibitor, a cholesterolabsorption inhibitor, an ileum sodium ion/bile acid co-transporterinhibitor, an up-regulator of LDL receptor activity, a nicotinichypolipidemic drug, a bile acid chelate, or a combination thereof.

In still other embodiments, the lipid-lowering drug is pravastatin,simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin,rosuvastatin or a combination thereof.

In other aspect, provided herein is use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for inhibiting SGLT1 in humans or animals.

In other aspect, provided herein is use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for improving the intestinal environment.

In other aspect, provided herein is use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for preventing or treating a disease, lessening a diseasesymptom or delaying the progression or onset of a disease, wherein thedisease is diabetes, diabetic complication, insulin resistance,hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity, syndrome X,atherosclerosis, cardiovascular disease, congestive heart failure,hypomagnesemia, hyponatremia, renal failure, disorders related to bloodconcentration, constipation, or high blood pressure.

In some embodiments, the diabetic complication is diabetic retinopathy,diabetic neuropathy or diabetic nephropathy.

In some embodiments, the hyperlipidemia is hypertriglyceridemia.

In another aspect, provided herein is a method of inhibiting SGLT1activity comprising administering to the patient a therapeuticallyeffective amount of the compound or the pharmaceutical compositiondisclosed herein.

In another aspect, provided herein is a method of improving theintestinal environment comprising administering to the patient atherapeutically effective amount of the compound or the thepharmaceutical composition disclosed herein.

In another aspect, provided herein is a method of preventing or treatinga disease comprising administering to the patient a therapeuticallyeffective amount of the compound or the the pharmaceutical compositiondisclosed herein, wherein the disease is diabetes, diabetescomplications, insulin resistance, hyperglycemia, hyperinsulinemia,hyperlipidemia, obesity, syndrome X, atherosclerosis, cardiovasculardisease, congestive heart failure, hypomagnesemia, hyponatremia, renalfailure, disorders related to blood concentration, constipation, or highblood pressure. Moreover, the above-mentioned compound or pharmaceuticalcomposition provided by the present invention can be co-administeredwith other therapies or therapeutic agents. The mode of administrationcan be simultaneous, sequential or at certain time intervals.

The dosage of the compound or pharmaceutical composition required forthe implementation of treatment, prevention or delay is usuallydependent on the specific compound administered, the patient, thespecific disease or condition and its severity, the route and frequencyof administration, etc., and it needs to be determined by the attendingphysician according to the specific situation. For example, when thecompound or pharmaceutical composition provided by the present inventionis administered by an intravenous route, it can be administered once aweek or even longer intervals.

In other aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in inhibiting SGLT1.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in improving the intestinalenvironment.

In other aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in preventing or treating adisease, lessening a disease symptom or delaying the progression oronset of a disease, wherein the disease is diabetes, diabetescomplications, insulin resistance, hyperglycemia, hyperinsulinemia,hyperlipidemia, obesity, syndrome X, atherosclerosis, cardiovasculardisease, congestive heart failure, hypomagnesemia, hyponatremia, renalfailure, disorders related to blood concentration, constipation, or highblood pressure.

In some embodiments, the salt refers to a pharmaceutically acceptablesalt. The term “pharmaceutically acceptable” means that the substance orcomposition must be chemically and/or toxicologically compatible withthe other ingredients comprising the formulation and/or the mammal beingtreated with it.

The compound of the present invention also includes other salt of suchcompound, which is not necessarily pharmaceutically acceptable salt, andcan be used as an intermediate for preparing and/or purifying thecompound of the invention and/or for separating an enantiomer of thecompound of the present invention.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, lauryl sulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, subsalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable. Lists of additional suitable salts can be found, e.g., in“Remington's Pharmaceutical Sciences”, 20th ed., Mack PublishingCompany, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization. The compounds of thepresent invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.

Any formula given herein is also intended to represent isotopicallyunenriched forms as well as isotopically enriched forms of thecompounds. Isotopically enriched compounds have the structure depictedby the general formula given herein, except that one or more atoms arereplaced by the atom having a selected atomic mass or mass number.Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, sulfur, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁶S, ³⁷Cl or ¹²⁵I, respectively.

In another aspect, the compounds of the invention include isotopicallyenriched compounds as defined herein, for example those into whichradioactive isotopes, such as 3H, 14c and ¹⁸F, or those into whichnon-radioactive isotopes, such as ²H and ¹³C are present. Suchisotopically enriched compounds are useful in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. An ¹⁸F-enriched compound may be particularly desirable for PETor SPECT studies. Isotopically-enriched compounds of Formula (I) cangenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described in theaccompanying Examples and Preparations using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability. For example, increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of Formula (I). The concentration of such aheavier isotope, specifically deuterium, may be defined by the isotopicenrichment factor. The term “isotopic enrichment factor” as used hereinmeans the ratio between the isotopic abundance and the natural abundanceof a specified isotope. If a substituent in a compound of this inventionis denoted deuterium, such compound has an isotopic enrichment factorfor each designated deuterium atom of at least 3500 (52.5% deuteriumincorporation at each designated deuterium atom), at least 4000 (60%deuterium incorporation), at least 4500 (67.5% deuterium incorporation),at least 5000 (75% deuterium incorporation), at least 5500 (82.5%deuterium incorporation), at least 6000 (90% deuterium incorporation),at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%deuterium incorporation), at least 6600 (99% deuterium incorporation),or at least 6633.3 (99.5% deuterium incorporation). Pharmaceuticallyacceptable solvates in accordance with the invention include thosewherein the solvent of crystallization may be isotopically substituted,e.g., D₂O, d₆-acetone, DMSO-d₆.

The foregoing merely summarizes certain aspects disclosed herein and isnot intended to be limiting in nature. These aspects and other aspectsand embodiments are described more fully below.

Composition of the Compound of the Invention and Preparations andAdministration

The present invention relates to a pharmaceutical composition comprisingthe compound of the present invention or the compound of the structureshown in the examples, or a stereoisomer, a geometric isomer, atautomer, an N-oxide, a solvate, a metabolite, a dimer, a trimer, apharmaceutically acceptable salt or a prodrug thereof. Thepharmaceutical composition further comprises at least onepharmaceutically acceptable carrier, excipient, adjuvant, vehicle or acombination thereof, and, optionally, other therapeutic and/orprophylactic ingredients. The amount of the compound in thepharmaceutical compositions disclosed herein is an effective anddetectable amount for inhibiting sodium-dependent glucose transporters(SGLTs), especially SGLT1 activity.

It will also be appreciated that certain of the compounds disclosedherein can exist in free form for treatment, or where appropriate, as apharmaceutically acceptable derivative thereof. Some non-limitingexamples of the pharmaceutically acceptable derivative includepharmaceutically acceptable prodrugs, salts, esters, salts of suchesters, or any other adducts or derivatives which upon administration toa patient in need is capable of providing, directly or indirectly, acompound as otherwise described herein, or a metabolite or residuethereof.

Pharmaceutically acceptable carriers may contain inert ingredients thatdo not unduly inhibit the biological activity of the compound. Thepharmaceutically acceptable carrier should be biocompatible, forexample, non-toxic, non-inflammatory, non-immunogenic or onceadministered to the patient without other adverse reactions or sideeffects. Standard pharmaceutical technology can be used.

As described above, the pharmaceutical compositions or pharmaceuticallyacceptable compositions disclosed herein further comprise apharmaceutically acceptable carrier, an adjuvant, or a vehicle, which,as used herein, includes any and all solvents, diluents, liquid vehicle,dispersion or suspension aids, surface active agents, isotonic agents,thickening or emulsifying agents, preservatives, solid binders,lubricants and the like, as suited to the particular dosage formdesired. Remington: The Science and Practice of Pharmacy, 21st edition,2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, andEncyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C.Boylan, 1988-1999, Marcel Dekker, New York, the contents of each ofwhich is incorporated by reference herein, are disclosed variouscarriers used in formulating pharmaceutically acceptable compositionsand known techniques for the preparation thereof. Except insofar as anyconventional carrier medium incompatible with the compounds disclosedherein, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any other componentsof the pharmaceutically acceptable composition, any other conventionalcarrier medium and its use are also contemplated to be within the scopeof this invention.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as Tween 80, phosphates, glycine,sorbic acid, or potassium sorbate, partial glyceride mixtures ofsaturated vegetable fatty acids, water, salts or electrolytes, such asprotamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, zinc salts, colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, methyl cellulose,hydroxypropyl methyl cellulose, wool fat, sugars such as lactose,glucose and sucrose; starches such as corn starch and potato starch;cellulose and its derivatives such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate; powdered tragacanth; malt;gelatin; talc; excipients such as cocoa butter and suppository waxes;oils such as peanut oil, cottonseed oil; safflower oil; sesame oil;olive oil; corn oil and soybean oil; glycols; such a propylene glycol orpolyethylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

The compounds or compositions of the present invention can beadministered by any suitable means, and the compounds and thepharmaceutically acceptable compositions described above can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, drops or patch), bucally, as an oral or nasal spray,or the like, depending on the severity of the infection being treated.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredient,the liquid dosage forms may contain inert diluent commonly used in theart, such as, for example, water or other solvents, solubilizing agentsand emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof. In addition to the inertdiluent, the oral compositions may also contain adjuvants such aswetting agents, emulsifying or suspending agents, sweetening agents,flavoring agents and fragrances.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Theacceptable vehicles and solvents that include water, Ringer's solution,U. S. P. and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose, any bland fixed oil can be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound or a composition describedherein, it is often desirable to slow the absorption of the compoundfrom subcutaneous or intramuscular injection. This may be accomplishedby the use of a liquid suspension of crystalline or amorphous materialhaving poor water solubility. The rate of absorption of the drug thendepends upon its rate of dissolution which, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolic acid. Depending upon the ratioof compound to polymer and the nature of the particular polymeremployed, the rate of compound release can be controlled. Examples ofother biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the compound in liposomes or microemulsions that arecompatible with body tissues.

Compositions for rectal or vaginal administration are specificallysuppositories which can be prepared by mixing the compounds describedherein with suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol or a suppository wax which are solid atambient temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

The solid dosage forms for oral administration include capsules,tablets, pills, powders and granules. In such solid dosage forms, theactive compounds are mixed with at least one pharmaceutically acceptableinert excipients or carriers, such as sodium citrate or calciumphosphate and/or (a) fillers or swelling agents such as starch, lactose,sucrose, glucose, mannitol and silicic acid; (b) adhesives such ascarboxymethylcellulose, alginates, gelatin, polyethylene pyrrole ketone,sucrose and gum arabic; (c) moisturizing agents such as glycerol; (d)disintegrating agents such as agar, calcium carbonate, potato starch ortapioca starch, alginic acid, certain silicates and sodium carbonate;(e) blocker solution, such as paraffin; (f) absorption promoter such asquaternary ammonium compounds; (g) wetting agents such as cetyl alcoholand glycerol monostearate; (h) absorbents such as kaolin and bentonite,(i) lubricants such as talc, calcium stearate, magnesium stearate, solidpolyethylene glycol, laurylsodium sulfate, and mixtures thereof. In thecase of capsules, tablets and pills, the pharmaceutical compositions mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, controlled release coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms, the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such asmagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the pharmaceutical compositions may alsocomprise buffering agents. They may optionally contain opacifying agentsand can also be of a composition that they release the activeingredient(s) only, or preferentially, in a certain part of theintestinal tract, optionally, in a delayed manner. Examples of embeddingcompositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compounddescribed herein include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active ingredientis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any necessary preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

The compositions described herein may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes, but is not limited to, subcutaneous,intravenous, intramuscular, intra-articular, intra-synovial,intrasternal, intrathecal, intrahepatic, intralesional and intracranialinjection or infusion techniques. Specifically, the compositions areadministered orally, intraperitoneally or intravenously.

Sterile injectable forms of the compositions described herein may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilcan be employed including synthetic mono- or diglycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

The pharmaceutical compositions described herein may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include, but arenot limited to, lactose and corn starch. Lubricating agents, such asmagnesium stearate, are also typically added. For oral administration ina capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening, flavoring or coloring agents may also beadded.

Alternatively, the pharmaceutical compositions described herein may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include, but are not limited to, cocoa butter, beeswaxand polyethylene glycols.

The pharmaceutical compositions described herein may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carrier compounds fortopical administration of the present invention include, but are notlimited to, mineral oil, petrolatum oil, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxesand water. Alternatively, the pharmaceutical compositions can beformulated in a suitable lotion or cream containing the activecomponents suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Suitable carriers include, but are not limited to,mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,specifically, as solutions in isotonic, pH adjusted sterile saline,either with or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions may also be administered by nasalaerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other conventional solubilizing or dispersingagents.

The compounds for use in the methods of the invention can be formulatedin unit dosage form. The term “unit dosage form” refers to physicallydiscrete units suitable as unitary dosage for subjects undergoingtreatment, with each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect,optionally in association with a suitable pharmaceutical carrier. Theunit dosage form can be for a single daily dose or one of multiple dailydoses (e.g., about 1 to 4 or more times per day). When multiple dailydoses are used, the unit dosage form can be the same or different foreach dose.

Compounds disclosed herein can be administered as the solepharmaceutical agent or in combination with one or more other additionaltherapeutic (pharmaceutical) agents where the combination causes nounacceptable adverse effects. This may be of particular relevance forthe treatment of diabetes, diabetic complications and other relateddiseases. Some non-limiting examples of these diseases include diabetesmellitus type I, diabetes type II, diabetic retinopathy, diabeticneuropathy, diabetic nephropathy, insulin resistance, hyperglycemia,hyperinsulinemia, elevated blood levels of fatty acids or glycerol,hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabeticcomplications, atherosclerosis, cardiovascular disease, congestive heartfailure, hypomagnesemia, hyponatremia, renal failure, disorders relatedto blood concentration, constipation, or hypertension. The “additionaltherapeutic agent” used in the present invention includes ananti-diabetic drug, an anti-hyperglycemic drug, an anti-obesity drug, ananti-hypertensive drug, an appetite suppressing drug, a lipid-loweringdrug, or a combination thereof.

Wherein, the anti-diabetic agent includes, but is not limited to, aSGLT2 inhibitor (e.g., dapagliflozin, canagliflozin, tofogliflozin,ipragliflozin, luseogliflozin, empagliflozin), a biguanide drug (e.g.,phenformin, metformin), a sulfonylurea drug (e.g., acetohexamide,chlorpropamide, glibenclamide, glipizide, gliclazide, glimepiride,glipentide, gliquidone, tolazamide, tolbutamide and meglitinide), aglinides drug (e.g., repaglinide and nateglinide), an α-glucosidehydrolase inhibitor (e.g., acarbose), an α-glucosidase inhibitor (e.g.,adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin,salbostatin), a PPAR agonist (e.g., bagliglitazone, ciglitazone,darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone andtroglitazone), a PPARα/γ dual agonist (such as CLX-0940, GW-1536,GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), adipeptidyl peptidase IV (DPP-IV) inhibitor (e.g., sitagliptin,vidagliptin, alogliptin, linagliptin and saxagliptin), a glucagon-likepeptide-1(GLP-1) agonist (e.g., exendin-3 and exendin-4), a proteintyrosine phosphatases-1B (PTP-1B) inhibitor (e.g., trodusquemine,hyrtiosal extract and compounds are disclosed by Zhang, S. et al., DrugDiscovery Today, 12(9/10), 373-381, 2007), insulin, an insulin mimetic,a glycogen phosphorylase inhibitor, a VPAC2 receptor agonist, aglucokinase activator, a glycogen phosphorylase inhibitor, aglucose-6-phosphatase inhibitor, an αP2 inhibitor, an acetyl-CoAcarboxylase-2 (ACC-2) inhibitor, a phosphodiesterase (PDE)-10 inhibitor,a diacylglycerol acyltransferase (DGAT) 1 or 2 inhibitor, a glucosetransporter 4 (GLUT4) regulator and a glutamine-fructose-6-phosphateamidotransferase (GFAT) inhibitor.

Wherein, the antihyperglycemic agent includes, but is not limited to, aSGLT2 inhibitor (e.g., dapagliflozin, canagliflozin, tofogliflozin,ipragliflozin, luseogliflozin, empagliflozin), a biguanide drug (e.g.,phenformin and metformin), a sulfonylurea drug (e.g., acetohexamide,chlorpropamide, glibenclamide, glipizide, gliclazide, glimepiride,glipentide, gliquidone, tolazamide, tolbutamide and meglitinide), aglinides drug (e.g., repaglinide, nateglinide), an α-glucoside hydrolaseinhibitor (e.g., acarbose), an α-glucosidase inhibitor (e.g., adiposine,camiglibose, emiglitate, miglitol, voglibose, pradimicin andsalbostatin), a PPAR agonist (e.g., balaglitazone, ciglitazone,darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone andtroglitazone), a PPARα/γ dual agonist (such as CLX-0940, GW-1536,GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), adipeptidyl peptidase IV (DPP-IV) inhibitor (e.g., sitagliptin,vidagliptin, alogliptin and saxagliptin), a glucagon-likepeptide-1(GLP-1) agonist (e.g., exendin-3 and exendin-4), a proteintyrosine phosphatases-1B (PTP-1B) inhibitor (e.g., trodusquemine,hyrtiosal extract and compounds are disclosed by Zhang, S. et al., DrugDiscovery Today, 12(9/10), 373-381, 2007), insulin, an insulin mimetic,a glycogen phosphorylase inhibitor, a VPAC2 receptor agonist, aglucokinase activator, a glycogen phosphorylase inhibitor, aglucose-6-phosphatase inhibitor, an αP2 inhibitor, an acetyl-CoAcarboxylase-2 (ACC-2) inhibitor, a phosphodiesterase (PDE)-10 inhibitor,a diacylglycerol acyltransferase (DGAT) 1 or 2 inhibitor, a glucosetransporter 4 (GLUT4) regulator and a glutamine-fructose-6-phosphateamidotransferase (GFAT) inhibitor.

Wherein, the anti-obesity drug of the present invention includes, but isnot limited to a central anti-obesity drug (such as dexfenfluramine,fenfluramine, phentermine, sibutramine, amfepramone, d-amphetamine,mazidol, phenylpropanolamine, clobenzorex, a MCH receptor antagonist(e.g., compounds described in WO06035967, SB-568849; SNAP-7941,T-226296), a neuropeptide Y receptor antagonist (e.g., CP-422935), acannabinoid receptor antagonist (e.g., rimonabant, SR-147778), acerebrointestinal peptide antagonist, a lipase inhibitor (e.g.,orlistat, ATL-962), a β3 agonist (e.g., AJ-9677, AZ40140), a 11β-HSD1inhibitor (e.g., BVT-3498, INCB13739), a DGAT-1 inhibitor, peptideappetite suppressants (e.g., leptin, CNTF (ciliary neurotrophicfactor)), a cholecystokinin agonist (e.g., lintitript)) and a feedinginhibitor (e.g., P-57).

Wherein, the lipid-lowering agent includes, but is not limited to, anMTP inhibitor, an HMGCoA reductase inhibitor, a squalene synthaseinhibitor, a fibrate hypolipidemic drug (betinic acid-type hypolipidemicdrug), an ACAT inhibitor, a lipoxygenase inhibitor, a cholesterolabsorption inhibitor, an ileal Na(+)/bile acid cotransporter inhibitor,an upregulators of LDL receptor activity, a bile acid sequestrant or anicotinic acid hypolipidemic drug In some embodiments, thelipid-lowering agent is selected from pravastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, atavastatin and rosuvastatin.Wherein, the anti-obesity agent includes a CB-1 antagonist (such asrimonabant, taranabant, surinabant, otenabant, SLV319 and AVE1625), agut-selective MTP inhibitor (such as dirlotapide, mitratapide andimplitapide), a CCKa agonist, a 5-HT2c agonist (such as lorcaserin), aMCR4 agonist, a lipase inhibitor (such as cetilistat), PYY3-36, anopioid antagonist (such as naltrexone), oleoyl-estrone, obinepitide,pramlintide, tesofensine, leptin, liraglutide, bromocriptine, orlistat,exenatide, AOD-9604 and sibutramide.

Wherein, the suitable anti-inflammatory agent includes genitaltract/urinary tract infection preventative and treatment. Exemplaryagent includes cranberry (Vaccinium macrocarpon) and cranberryderivative, such as cranberry juice, cranberry extract or flavonol ofcranberry. Moreover, other suitable anti-inflammatory agent includes,but is not limited to, aspirin, a non-steroidal anti-inflammatory drug,glucocorticosteroid, sulfasalazine and a selective cyclooxygenase-2inhibitor, etc.

Use of the Compounds and Pharmaceutical Compositions

The amount of the compound or the compound in the compositions disclosedherein is an effective and detectable amount for inhibitingsodium-dependent glucose transporters (SGLTs) activity, especially SGLT1activity. Hence, the compound of the invention would be used forpreventing and treating diabetes and related diseases or improvingsymptoms of these diseases.

Compounds disclosed herein would be useful for, but are not limited to,preventing or treating diabetes or related diseases, or lesseningdiabetes or related diseases, or delaying the progression or onset ofdiabetes or related diseases or increasing HDL levels in a patient byadministering to the patient a compound or a composition disclosedherein in an effective amount. Such diseases include, but are notlimited to diabetes, especially type 2 diabetes, and insulin resistance,hyperglycemia, hyperinsulinemia, hyperlipidemia such ashypertriglyceridemia, diabetic complications such as diabeticretinopathy, diabetic neuropathy or diabetic nephropathy, obesity,syndrome X, atherosclerosis, cardiovascular disease, congestive heartfailure, hypomagnesemia, hyponatremia, renal failure, disorders relatedto blood concentration, constipation or high blood pressure.

The compound of the present invention has an excellent intestinalenvironment improvement effect, which can increase the beneficialbacteria of bifidobacteria, Lactobacillus, etc., increase the organicacid in the intestine, and reduce the spoilage products in theintestine. By covering the intestinal environment, diseases associatedwith changes in the intestinal environment can be improved. The “diseaseassociated with changes in the intestinal environment” includes, but isnot limited to, chronic kidney disease, pseudomembranousenteritis/hemorrhagic enteritis, infectious enteritis, ulcerativecolitis, Crohn's disease, irritable bowel syndrome, obesity,arteriosclerosis, hypertension, Guillain-Barré syndrome, allergicdiseases, diabetes, multiple sclerosis, autoimmune diseases, alcoholicliver dysfunction, nonalcoholic fatty liver disease, nonalcoholic fattyhepatitis, non-steroidal anti-inflammatory drug-induced enteritis,stress, depression, influenza, periodontal disease, cancer, hay fever,functional dyspepsia, pruritus, etc.

Moreover, compounds or pharmaceutical compositions disclosed herein alsosuit for preventing or treating the damage of diabetes in later stages,such as kidney disease, retinopathy, neuropathy, myocardial infarction,peripheral arterial disease, thrombosis, arteriosclerosis, inflammation,immunological diseases, autoimmune diseases such as AIDS, asthma,osteoporosis, cancer, psoriasis, Alzheimer's disease, schizophrenia andinfectious diseases.

An “effective amount” or “effective dose” of the compound orpharmaceutically acceptable composition is an amount that is effectivein treating or lessening the severity of one or more of theaforementioned disorders. The compounds and pharmaceutically acceptablecompositions are effective administered in a fairly wide dose range. Forexample, the daily dose is from about 0.1 mg to 1000 mg per person, thecompounds or pharmaceutically acceptable compositions can beadministered in a single dose or in several divided doses a day. Thecompounds and compositions, according to the method disclosed herein,may be administered using any amount and any route of administrationwhich is effective for treating or lessening the severity of thedisorder or disease. The exact amount required will vary from subject tosubject, depending on the species, age, and general condition of thesubject, the severity of the infection, the particular agent, its modeof administration, and the like. A compound or composition can also beadministered with one or more other therapeutic agents as discussedabove.

General Synthesis and Detection Methods

To describe the invention, the following examples are listed. However,it should be understood that the present invention is not limited tothese embodiments, but merely provides a method for practicing thepresent invention.

In the present invention, if the chemical name of the compound doesn'tmatch the corresponding structure, the compound is characterized by thecorresponding structure.

Generally, the compounds disclosed herein may be prepared by methodsdescribed herein, wherein the substituents are as defined for Formula(I), Formula (I-a) or Formula (II) above, except where further noted.The following non-limiting schemes and examples are presented to furtherexemplify the invention.

Persons skilled in the art will recognize that the chemical reactionsdescribed may be readily adapted to prepare a number of other compoundsdisclosed herein, and alternative methods for preparing the compoundsdisclosed herein are deemed to be within the scope disclosed herein. Forexample, the synthesis of non-exemplified compounds according to theinvention may be successfully performed by modifications apparent tothose skilled in the art, e.g., by appropriately protecting interferinggroups, by utilizing other suitable reagents known in the art other thanthose described, and/or by making routine modifications of reactionconditions. Alternatively, other reactions disclosed herein or known inthe art will be recognized as having applicability for preparing othercompounds disclosed herein.

The structures of the compounds were identified by nuclear magneticresonance (e.g., ¹H-NMR, ¹³C-NMit or/and ¹⁹F-NMR). ¹H-NMR, ¹³C-NMitor/and ¹⁹F-NMR chemical shifts (6) were recorded as ppm (10⁻⁶). ¹H-NMR,¹³C-NMR, and ¹⁹F-NMit were measured with Bruker Ultrashield-400 nuclearmagnetic resonance spectrometer and Bruker Avance III HD 600 nuclearmagnetic resonance spectrometer. The determination solvent is deuteratedchloroform (CDCl₃), deuterated methanol (CD₃OD or MeOH-d₄) or deuterateddimethyl sulfoxide (DMSO-d₆). TMS (0 ppm) or chloroform (7.25 ppm) wasused as the reference standard. When peak multiplicities are reported,the following abbreviations are used: s (singlet), d (doublet), t(triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt(doublet of triplets), td (triplet of doublets), brs (broadenedsinglet). Coupling constants J, when given, were reported in Hertz (Hz).

Novasep pump 250 high performance liquid chromatograph was generallyused for preparative purification or preparative resolution.

LC-MS spectra were determined on Agilen-6120 Quadrupole LC/MS massspectrometer;

The silica gel used in column chromatography generally was Qingdao OceanChemical Factory 300 to 400 mesh silica gel.

The staring materials of the present invention were known or purchasedfrom Shanghai Accela Company, Energy Company, J&K, Alfa Company and thelike, or they could be prepared by the conventional synthesis methods inthe prior art.

Unless otherwise stated, the reactions disclosed herein were carried outin a nitrogen atmosphere.

The term “nitrogen atmosphere” refers to such an atmosphere that areaction flask was equipped with a balloon or a stainless steelautoclave filled with about 1 L nitrogen.

The term “hydrogen atmosphere” refers to such an atmosphere that areaction flask was equipped with a balloon or a stainless steelautoclave filled with about 1 L hydrogen.

Unless otherwise stated, the solution used in the examples disclosedherein was an aqueous solution.

Unless otherwise stated, the reaction temperature was room temperature.

Unless otherwise stated, the room temperature was from 20° C. to 30° C.

The reaction process in the examples was monitored by thin layerchromatography (TLC). The solvent system for development of a TLC platecomprised dichloromethane and methanol, dichloromethane and ethylacetate, petroleum ether and ethyl acetate. The volume ratio of thesolvents in the solvent system was adjusted according to the polarity ofthe compounds.

The elution system of column chromatography comprised: A: petroleumether and ethyl acetate, B: dichloromethane and ethyl acetate, C:dichloromethane and methanol. The volume ratio of the solvents in theelution system was adjusted according to the polarity of the compounds,and sometimes it was also adjusted by adding a basic agent such asaqueous ammonia or an acidic agent such as acetic acid.

The following abbreviations are used throughout the specification:

DMSO-d₆: deuterated dimethyl CDCl₃: chloroform-d; CD₃OD: methanol-d;sulfoxide; D₂O: deuterated water Allyl: allyl; Br: bromine; Mg:magnesium; Cbz: benzyloxycarbonyl; Ac: acetyl; Bn: benzyl; Et: ethyl;Me: methyl; Ms: methanesulfonyl; Boc: tert-butoxycarbonyl; PMB:p-methoxybenzyl; HCl: hydrogen chloride; MeOH: methanol; mL: milliliter;μL: microliter; M, mol/L: mole/liter; mmol: millimoles; g: gram; mol:mole; h: hour; H₂: hydrogen; min: minute; N₂: nitrogen; MPa: megapascal;atm: standard atmospheric DCM: methylene chloride; pressure; HBTU:O-benzotriazole-tetramethylurea hexafluorophosphate; HATU:O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphate;DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene.

General Synthetic Procedures

The typical synthetic steps for preparing the compounds disclosed in thepresent invention are shown in the following synthetic schemes 1 to 6.Unless otherwise stated, R², R³, R⁶, R⁷, R^(c), X^(d) and t are asdefined herein.

The intermediate having formula (6) can be synthesized by the methoddisclosed in synthesis scheme 1. First, compound (1) can react withbenzyl chloroformate to give compound (2). Compound (2) and compound (3)can be subjected to a condensation reaction to give compound (4). Then,compound (4) can remove the Cbz protecting group on the amino group bycatalytic hydrogenation to produce compound (5). Finally, compound (5)can form a salt with hydrogen chloride to give compound (6).

The intermediate having formula (10) can be synthesized by the methoddisclosed in synthesis scheme 2. First, compound (7) can be reduced witha reducing agent to give compound (8). Then, compound (8) and allylbromide can be subjected to a substitution reaction under basicconditions to give compound (9). Finally, compound (9) can react withmetal Mg to give compound (10).

The intermediate having formula (15) can be synthesized by the methoddisclosed in synthesis scheme 3. First, compound (11) can react withoxalyl chloride to give compound (12).

Then, compound (12) can react with dimethylolamine hydrochloride underbasic conditions to give compound (13). Next, compound (13) and thecompound (10) can be subjected to Grignard reaction to give compound(14). Finally, compound (14) can be subjected to a reduction reaction inthe presence of acid and triethylsilane to give compound (15).

The intermediate having formula (29) or (30) can be synthesized by themethod disclosed in synthesis scheme 4. First, compound (16) can besubjected to catalytic oxidation in the presence of2,2,6,6-tetramethylpiperidine oxide to give compound (17). Compound (17)can react with acetic anhydride to give compound (18). Compound (15) canreact with isopropylmagnesium chloride and then react with compound (18)through Grignard reaction to form compound (19). Compound (19) can reactwith methanol under acidic conditions to give compound (20). Compound(20) can be oxidized by oxidant to give compound (21). Compound (21) canreact with formaldehyde in the presence of DBU to give compound (22).Then, compound (22) can be subjected to a reduction reaction with sodiumborohydride to give compound (23). Compound (23) can be subjected to aring closing reaction under acidic conditions to give compound (24).Compound (24) can be oxidized with Dess Martin oxidant to give compound(25). Compound (25) can react with methanol under acidic conditions togive compound (26). Next, compound (26) can react with Grignard reagentunder low temperature to give compound (27). Compound (27) can removethe hydroxy protecting group allyl in the presence of a catalyst to givecompound (28). Finally, compound (28) can be oxidized with iodobenzenediacetic acid in the presence of catalyst 2,2,6,6-tetramethylpiperidineoxide to give compound (29). Compound (29) can be removed the hydroxyprotecting group Bn by catalytic hydrogenation to give compound (30).

The compound having formula (32) can be synthesized by the methoddisclosed in synthesis scheme 5. First, compound (29) and compound canbe subjected to a condensation reaction to give compound (31). Then,compound (31) can be removed the hydroxy protecting group Bn bycatalytic hydrogenation to give compound (32).

The compound having formula (32) can also be synthesized by the methoddisclosed in synthesis scheme 6. First, compound (30) can react withacetic anhydride under basic conditions to give compound (33). Next,compound (33) and compound can be subjected to a condensation reactionto give compound 04). Finally, compound (34) can be removed hydroxyprotecting group Ac under basic conditions to give compound (32).

EXAMPLES Example 12-Methyl-2-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyrylamino]-N-(2-pyrrolidin-1-ylethyl)propionamide

Step 1: BenzylN-[1,1-dimethyl-2-oxo-2-(2-pyrrolidin-1-ylethylamino)ethyl]carbamate

2-(Benzyloxycarbonylamino)-2-methyl-propionic acid (3.0 g, 13 mmol) wasdissolved in dichloromethane (30 mL) at room temperature. The mixturewas cooled to 0° C., and HATU (5.6 g, 14 mmol) andN,N-diisopropylethylamine (7.0 mL, 40 mmol) were added. The resultingmixture was stirred for 20 minutes. 2-Pyrrolidin-1-ylethylamine (1.9 g,17 mmol) was added, and the mixture was warmed to room temperature andstirred overnight. The resulting mixture was washed with water (20 mL),dried over anhydrous sodium sulfate, and filtered with suction. Thefiltrate was concentrated in vacuo and the residue was purified bysilica gel column chromatography (DCM/anhydrous MeOH (v/v)=30/1) to givethe title compound (2.2 g, yellow oil) in 52% yield.

MS (ESI, pos. ion) m/z: 334.4 [M+H]⁺.

Step 2: 2-Amino-2-methyl-N-(2-pyrrolidin-1-ylethyl)propanamide

To a mixed solution of benzylN-[1,1-dimethyl-2-oxo-2-(2-pyrrolidin-1-ylethylamino)ethyl]carbamate(2.0 g, 6.0 mmol) in tetrahydrofuran (2 mL) and anhydrous methanol (20mL) was added 10% Palladium/carbon (0.20 g, 0.18 mmol) at roomtemperature. The mixture was stirred overnight under a hydrogenatmosphere. The mixture was filtered with suction and concentrated invacuo to give the title compound (1.2 g, yellow oil) in 99% yield.

Step 3: 2-Amino-2-methyl-N-(2-pyrrolidin-1-ylethyl)propionamidedihydrochloride

To a solution of 2-amino-2-methyl-N-(2-pyrrolidin-1-ylethyl)propionamide(1.2 g, 6.0 mmol) in ethyl acetate (20 mL) was added HCl isopropanolsolution (4 mL, 5 M) at room temperature. The mixture was stirred for 1hour. The mixture was filtered with suction, the filter cake was washedwith ethyl acetate (20 mL), and dried in vacuo to give the titlecompound (1.2 g, white solid) in 73% yield.

MS (ESI, pos. ion) m/z: 200.3 [M+H]⁺.

¹H NMR (400 MHz, D₂O) δ (ppm): 3.65 (m, 2H), 3.56 (t, 2H), 3.33 (t, 2H),3.06 (m, 2H), 2.08 (m, 2H), 1.95 (m, 2H), 1.54 (s, 6H).

Step 4: 4-(4-bromophenyl)butyl-1-ol

4-(4-Bromophenyl)butanoic acid (50.0 g, 150 mmol) was dissolved intetrahydrofuran (250 mL) at room temperature, The mixture was cooled to−10° C. under a nitrogen atmosphere, then a solution of borane intetrahydrofuran (1.0 M, 300 mL, 300 mmol) was added. The resultingmixture was warmed to room temperature and stirred for 2 hours. Themixture was poured into ice water (500 mL) and extracted with ethylacetate (500 mL). The organic phases were washed with saturated brine(200 mL), dried over anhydrous sodium sulfate, filtered with suction andconcentrated in vacuo to obtain the title compound (47.0 g, colorlessoil) in 98% yield.

Step 5: 1-(4-allyloxybutyl)-4-bromo-benzene

4-(4-Bromophenyl)butyl-1-ol (47.0 g, 205 mmol) was dissolved intetrahydrofuran (500 mL) at room temperature. The mixture was cooled to−10° C. under a nitrogen atmosphere, and sodium hydride (11.0 g, 275mmol) was added in portions. The mixture was continued stirring for 30minutes, then allyl bromide (33.6 g, 288 mmol) was added dropwise. Theresulting mixture was warmed to room temperature and stirred overnight.The mixture was poured into ice water (1.0 L) to quench the reaction.The resulting mixture was extracted with EA (500 mL). The organic phaseswere washed with saturated brine (200 mL), dried over anhydrous sodiumsulfate, filtered with suction, and concentrated in vacuo. The residuewas purified by silica gel column chromatography [ethylacetate/petroleum ether (v/v)=1/40] to give the title compound (33.0 g,colorless oil) in 60% yield.

Step 6: [4-(4-allyloxybutyl)phenyl]-magnesium bromide

To a reaction flask were added magnesium bar (6.4 g, 0.26 mol) andiodine (0.6 g, 2 mmol) in sequence at room temperature.1-(4-allyloxybutyl)-4-bromo-benzene (59.0 g, 219 mmol) was dissolved intetrahydrofuran (300 mL), and 10 mL of the solution was added to themixture in the reaction flask under a nitrogen atmosphere. The resultingmixture was heated until the reaction started (the color of iodinedisappeared), then the remaining solution was added dropwise, and themixture was stirred at 65° C. for 20 minutes to obtain the titlecompound (65 g, brown solution), which was directly used in the nextstep. The yield was calculated as 100%.

Step 7: 5-iodo-2-methyl-benzoyl chloride

5-Iodo-2-methyl-benzoic acid (50.0 g, 191 mmol) was dissolved indichloromethane (500 mL) at room temperature. The mixture was cooled to−10° C. under a nitrogen atmosphere, and oxalyl chloride (25 mL, 0.29mol) and N,N-dimethylformamide (1.5 mL, 19 mmol) were added in turn. Theresulting mixture was stirred overnight at room temperature. The mixturewas concentrated in vacuo to give the title compound (53 g, yellowsolid) in 100% yield.

Step 8: 5-idodo-N-methoxy-N,2-dimethyl-benzamide

To a reaction flask were added 5-iodo-2-methyl-benzoyl chloride (53.0 g,189 mmol), dimethylolamine hydrochloride (37.0 g, 379 mmol) anddichloromethane (500 mL) at room temperature. The mixture was cooled to0° C. under a nitrogen atmosphere, and triethylamine (106 mL, 761 mmol)was added dropwise. The resulting mixture was stirred at roomtemperature for 3.5 hours. The mixture was washed with saturated brine(500 mL), dried over anhydrous sodium sulfate, and filtered withsuction. The filtrate was concentrated in vacuo to give the titlecompound (54 g, yellow oil) in 93% yield.

MS (ESI, pos. ion) m/z: 306.0 [M+H]⁺.

Step 9: [4-(4-allyloxybutyl)phenyl]-5-iodo-2-methyl-phenyl)methyl ketone

At room temperature, a solution of5-iodo-N-methoxy-N,2-dimethyl-benzamide (50.0 g, 164 mmol) intetrahydrofuran (200 mL) was cooled to −20° C. under a nitrogenatmosphere, then [4-(4-allyloxybutyl)phenyl]-magnesium bromide (63.0 g,215 mmol) was added dropwise. The mixture was stirred at −20° C. for 1hour, and stirred at room temperature overnight. The mixture was cooledto 0° C., quenched dropwise with saturated ammonium chloride solution(400 mL), extracted with ethyl acetate (300 mL×2), and the combinedorganic phases were washed with saturated brine (300 mL), dried over ahydrous sodium sulfate and filtered with suction. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography [ethyl acetate/petroleum ether (v/v)=1/30] to give thetitle compound (59.0 g, colorless oil) in 83% yield.

Step 10: 2-[[4-(4-allyloxybutyl)phenyl]methyl]-4-iodo-1-methyl-benzene

To a reaction flask were added[4-(4-allyloxybutyl)phenyl]-5-iodo-2-methyl-phenyl) methyl ketone (59.0g, 136 mmol) and trifluoroacetic acid (150 mL) in turn at roomtemperature. The mixture was cooled to 0° C. under a nitrogenatmosphere, and then triethylsilane (174 mL, 1.09 mol) andtrifluoromethanesulfonic acid (12.5 mL, 141 mmol) were added dropwise inturn. The mixture was stirred at room temperature for 1 hour. Themixture was concentrated in vacuo, and the residue was dissolved inethyl acetate (600 mL), washed with water (500 mL), saturated sodiumbicarbonate solution (500 mL) and saturated brine (500 mL) in turn,dried over anhydrous sodium sulfate, and filtered with suction. Afterconcentration, the residue was purified by silica gel columnchromatography [petroleum ether] to obtain the title compound (57 g,yellow oil) in 99% yield.

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.52-7.47 (m, 2H), 7.13 (d, 2H), 7.04(d, 2H), 6.92 (d, 1H), 5.95 (m, 1H), 5.30 (dd, 1H), 5.20 (dd, 1H),4.02-3.97 (m, 2H), 3.91 (s, 2H), 3.48 (t, 2H), 2.64 (t, 2H), 2.21 (s,3H), 1.76-1.63 (m, 4H).

Step 11:(3R,4S,5R,6R)-3,4,5-tribenzyloxy-6-(benzyloxymethyl)tetrahydropyran-2-one

To a reaction flask were added(3R,4S,5R,6R)-3,4,5-tribenzyloxy-6-(benzyloxymethyl)tetrahydropyran-2-ol(130 g, 240 mmol), sodium bicarbonate (80.0 g, 952 mmol),dichloromethane (1000 mL) and water (800 mL) in turn at roomtemperature. The mixture was cooled to 0° C., potassium bromide (18.0 g,151 mmol) and 2,2,6,6-tetramethylpiperidine oxide (5.6 g, 36 mmol) wereadded, and then sodium hypochlorite solution (360 g, available chlorine6.2%, available chlorine 629 mmol) was added in one portion. The mixturewas stirred for 20 minutes. The layers were separated, and the organicphases were washed with saturated brine (500 mL), dried over anhydroussodium sulfate, filtered with suction, and concentrated in vacuo toobtain the title compound (129 g, yellow oil) in 100% yield.

Step 12: Methyl[(2R,3R,4S,5R)-3,4,5-tribenzyloxy-6-oxo-tetrahydropyran-2-yl] acetate

To a solution of(3R,4S,5R,6R)-3,4,5-tribenzyloxy-6-(benzyloxymethyl)tetrahydropyran-2-one(130 g, 241 mmol) in acetic anhydride (200 mL, 2.12 mol) was addedglacial acetic acid (350 mL) at room temperature. The mixture was cooledto −15° C. under the nitrogen atmosphere, then concentrated sulfuricacid (14.0 mL, 263 mmol) was added dropwise. The temperature wascontrolled at −15° C.˜−10° C. The mixture was stirred for 2.5 hours. Themixture was poured into ice water (1.5 L) and extracted with ethylacetate (1.0 L). The organic phases were washed successively with water(500 mL), saturated sodium bicarbonate solution (1.0 L) and saturatedbrine (500 mL), dried over anhydrous sodium sulfate, filter withsuction, and concentrated in vacuo. The residue was purified by silicagel column chromatography [ethyl acetate/petroleum ether (v/v)=1/4] togive the title compound (85 g, colorless oil) with a yield of 71%.

Step 13: Methyl[(2R,3R,4S,5R,6S)-6-[3-[[4-(4-allyloxybutyl)phenyl]methyl]-4-methyl-phenyl]-3,4,5-tribenzyloxy-6-hydroxy-tetrahydropyran-2-yl]acetate

2-[[4-(4-Allyloxybutyl)phenyl]methyl]-4-iodo-1-methyl-benzene (30.0 g,71.4 mmol) was dissolved in tetrahydrofuran (150 mL) at roomtemperature. The mixture was cooled to −10° C. under a nitrogenatmosphere, and a solution of isopropyl magnesium chloride intetrahydrofuran (39 mL, 78 mmol, 2.0 M) was added dropwise. The mixturewas stirred for 1.5 hours, and was added dropwise to a solution ofmethyl [(2R,3R,4S,5R)-3,4,5-tribenzyloxy-6-oxo-tetrahydropyran-2-yl]acetate (25.0 g, 50.9 mmol) in tetrahydrofuran (150 mL). The resultingmixture was stirred for 2.5 hours. The reaction mixture was quenchedwith saturated aqueous ammonium chloride (200 mL). The resulting mixturewas extracted with ethyl acetate (300 mL×2). The combined organic layerswere washed with saturated brine (500 mL), dried over a hydrous sodiumsulfate and filtered with suction. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography[ethyl acetate/petroleum ether (v/v)=1/4] to give the title compound(32.1 g, yellow oil) in 80% yield.

Step 14:[(2R,3R,4S,5R,6S)-6-[3-[[4-(4-Allyloxybutyl)phenyl]methyl]-4-methyl-phenyl]-3,4,5-tribenzyloxy-6-methoxy-tetrahydropyran-2-yl]methanol

Methyl[(2R,3R,4S,5R,6S)-6-[3-[[4-(4-allyloxybutyl)phenyl]methyl]-4-methyl-phenyl]-3,4,5-tribenzyloxy-6-hydroxy-tetrahydropyran-2-yl]acetate (28.0 g, 35.6 mmol) was dissolved in anhydrous methanol (300 mL)at room temperature. Then concentrated hydrochloric acid (9.0 mL, 0.11mol) was added and the mixture was stirred for 3 hours. The mixture wasadded with ethyl acetate (500 mL), washed successively with water (500mL), saturated sodium bicarbonate solution (200 mL) and saturated brine(200 mL), dried over anhydrous sodium sulfate, filtered by suction,concentrated, and the residue was purified by silica gel columnchromatography [ethyl acetate/petroleum ether (v/v)=1/4] to give thetitle compound (23.0 g, colorless oil) in 85% yield.

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.46-7.27 (m, 15H), 7.20-7.05 (m, 7H),5.99 (m, 1H), 5.35 (dd, 1H), 5.25 (t, 1H), 5.02 (dt, 3H), 4.81 (d, 1H),4.53 (d, 1H), 4.30 (t, 1H), 4.14-3.75 (m, 10H), 3.55-3.44 (m, 3H), 3.24(s, 3H), 2.67 (t, 2H), 2.34 (s, 3H), 1.79-1.67 (m, 4H).

Step 15:[(2S,3S,4S,5R,6S)-6-[3-[[4-(4-Allyloxybutyl)phenyl]methyl]-4-methyl-phenyl]-3,4,5-tribenzyloxy-6-methoxy-tetrahydropyran-2-yl]carbaldehyde

To a reaction flask were added[(2R,3R,4S,5R,6S)-6-[3-[[4-(4-allyloxybutyl)phenyl]methyl]-4-methyl-phenyl)-3,4,5-tribenzyloxy-6-methoxy-tetrahydropyran-2-yl]methanol(23.0 g, 30.4 mmol), sodium bicarbonate (16.0 g, 190 mmol),dichloromethane (250 mL) and water (160 mL) in turn at room temperature.The mixture was cooled to 0° C., then potassium bromide (2.4 g, 20mmol), 2,2,6,6-tetramethylpiperidine oxide (0.75 g, 4.8 mmol) and sodiumhypochlorite solution (52 g, available chlorine 5.53%, availablechlorine 81 mmol) were added in turn. The mixture was stirred for 15minutes. The layers were separated, and the organic phases were washedwith saturated brine (200 mL), dried over anhydrous sodium sulfate,filtered by suction and concentrated to obtain the title compound (22 g,yellow oil) in 96% yield.

Step 16:(2R,3S,4S,5R,6S)-6-[3-[[4-(4-Allyloxybutyl)phenyl]methyl]-4-methyl-phenyl]-3,4,5-tribenzyloxy-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde

[(2S,3S,4S,5R,6S)-6-[3-[[4-(4-Allyloxybutyl)phenyl]methyl]-4-methyl-phenyl]-3,4,5-tribenzyloxy-6-methoxy-tetrahydropyran-2-yl]carbaldehyde(23.0 g, 30.4 mmol) was dissolved in N,N-dimethylformamide (200 mL) atroom temperature, then the mixture was cooled to 0° C. 37% Formaldehydesolution (62.0 g, 764 mmol) and DBU (3.1 g, 20 mmol) were added. Theresulting mixture was warmed to room temperature and stirred overnight.The mixture was added with ethyl acetate (300 mL), washed successivelywith water (400 mL) and saturated brine (200 mL), dried over anhydroussodium sulfate, filtered by suction and concentrated to obtain the titlecompound (23.0 g, yellow oil) in 96% yield.

Step 17:[(3S,4S,5R,6S)-6-[3-[[4-(4-Allyloxybutyl)phenyl]methyl]-4-methyl-phenyl]-3,4,5-tribenzyloxy-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol

(2R,3S,4S,5R,6S)-6-[3-[[4-(4-Allyloxybutyl)phenyl]methyl]-4-methyl-phenyl]-3,4,5-tribenzyloxy-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde(23.0 g, 29.3 mmol) was dissolved in methanol (200 mL) at roomtemperature. Then the mixture was cooled to 0° C., and sodiumborohydride (2.8 g, 74 mmol) was added in portions. The resultingmixture was continued stirring for 10 minutes. The mixture was addedwith ethyl acetate (500 mL), washed successively with water (500 mL) andsaturated brine (200 mL), dried over anhydrous sodium sulfate, filteredby suction and concentrated to obtain the title compound (23.0 g, yellowoil) in 100% yield.

Step 18:[(1S,2S,3S,4R,5S)-5-[3-[[4-(4-Allyloxybutyl)phenyl]methyl]-4-methyl-phenyl]-2,3,4-tribenzyloxy-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol

[(3S,4S,5R,6S)-6-[3-[[4-(4-Allyloxybutyl)phenyl]methyl]-4-methyl-phenyl]-3,4,5-tribenzyloxy-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol(23.0 g, 29.2 mmol) was dissolved in tetrahydrofuran (150 mL) at roomtemperature, then p-toluenesulfonic acid monohydrate (7.0 g, 37 mmol)was added. The resulting mixture was stirred overnight. The mixture wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography [ethyl acetate/petroleum ether (v/v)=1/8)] to give thetitle compound (12.5 g, yellow oil) in 57% yield.

Step 19:(1S,2S,3S,4R,5S)-5-[3-[[4-(4-Allyloxybutyl)phenyl]methyl]-4-methyl-phenyl]-2,3,4-tribenzyloxy-6,8-dioxabicyclo[3.2.1]octane-1-carboxylic acid

[(1S,2S,3S,4R,5S)-5-[3-[[4-(4-Allyloxybutyl)phenyl]methyl]-4-methyl-phenyl]-2,3,4-tribenzyloxy-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol(12.5 g, 16.6 mmol) was dissolved in dichloromethane (130 mL) at roomtemperature, then the mixture was cooled to 0° C. Dess Martin oxidant(50.0 g, 117 mmol) was added. The resulting mixture was heated to 40° C.and reacted for 2 hours. The mixture was concentrated in vacuo, and theresidue was purified by silica gel column chromatography [ethylacetate/petroleum ether (v/v)=1/2] to give the title compound (10 g,white solid) in 78% yield.

Step 20: Methyl(1S,2S,3S,4R,5S)-5-[3-[[4-(4-allyloxybutyl)phenyl]methyl]-4-methyl-phenyl]-2,3,4-tribenzyloxy-6,8-dioxabicyclo[3.2.1]octane-1-carboxylate

(1S,2S,3S,4R,5S)-5-[3-[[4-(4-Allyloxybutyl)phenyl]methyl]-4-methyl-phenyl]-2,3,4-tribenzyloxy-6,8-dioxabicyclo[3.2.1]octane-1-carboxylicacid (10.0 g, 13.0 mmol) was dissolved in anhydrous methanol (100 mL) atroom temperature, then concentrated sulfuric acid (1.0 mL, 19 mmol) wasadded. The mixture was heated to 40° C. and stirred overnight. Themixture was added with ethyl acetate (200 mL), washed successively withwater (300 mL) and saturated sodium bicarbonate solution (100 mL), driedover anhydrous sodium sulfate, filtered by suction, concentrated, andthe residue was purified by silica gel column chromatography [ethylacetate/petroleum ether (v/v)=1/10] to give the title compound (7.5 g,colorless oil) in 74% yield.

Step 21:2-[(1S,2S,3S,4R,5S)-5-[3-[[4-(4-Allyloxybutyl)phenyl]methyl]-4-methyl-phenyl]-2,3,4-tribenzyloxy-6,8-dioxabicyclo[3.2.1]octan-1-yl]propane-2-ol

Methyl(1S,2S,3S,4R,5S)-5-[3-[[4-(4-allyloxybutyl)phenyl]methyl]-4-methyl-phenyl]-2,3,4-tribenzyloxy-6,8-dioxabicyclo[3.2.1]octane-1-carboxylate(7.5 g, 9.6 mmol) was dissolved in tetrahydrofuran (80 mL) at roomtemperature. The mixture was cooled to 0° C. under a nitrogenatmosphere, and methyl magnesium bromide ether solution (20 mL, 60 mmol,3.0 M) was added dropwise. The resulting mixture was warmed to roomtemperature and stirred for 4 hours. The mixture was cooled to 0° C.,quenched by dropwise addition of saturated ammonium chloride solution(100 mL), extracted with ethyl acetate (100 mL×2), and the combinedorganic phases were washed with saturated brine (100 mL), dried overanhydrous sodium sulfate, filtered by suction and concentrated to obtainthe title compound (7.5 g, colorless oil) in 99% yield.

Step 22:4-[4-[[2-Methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butane-1-ol

2-[(1S,2S,3S,4R,5S)-5-[3-[[4-(4-allyloxybutyl)phenyl]methyl]-4-methyl-phenyl]-2,3,4-tribenzyloxy-6,8-dioxabicyclo[3.2.1]octan-1-yl]propane-2-ol(7.0 g, 8.9 mmol) was dissolved in anhydrous methanol (80 mL) at roomtemperature, then palladium dichloride (1.0 g, 5.6 mmol) was added, andthe mixture was stirred at room temperature for 2 hours under a nitrogenatmosphere. The mixture was filtered by suction, concentrated, and theresidue was purified by silica gel column chromatography [ethylacetate/petroleum ether (v/v)=1/2] to obtain the title compound (5.1 g,colorless oil) in 77% yield.

Step 23:4-[4-[[2-Methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyricacid

4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butan-1-ol(2.0 g, 2.7 mmol) was dissolved in dichloromethane (20 mL) at roomtemperature, then water (4 mL), 2,2,6,6-tetramethylpiperidine oxide(0.13 g, 0.79 mmol) and (diacetoxyiodo)benzene (2.2 g, 6.7 mmol) wereadded. The mixture was stirred overnight. The layers were separated, andthe organic phases were dried over anhydrous sodium sulfate, filtered bysuction, concentrated, and the residue was purified by silica gel columnchromatography [ethyl acetate/petroleum ether (v/v)=1/2] to give thetitle compound (1.7 g, white solid) in 83% yield.

Step 24:2-Methyl-2-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyrylamino]-N-(2-pyrrolidin-1-ylethyl)propionamide

4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyricacid (0.80 g, 1.05 mmol) was dissolved in N, N-dimethylformamide (6 mL)at room temperature, then the mixture was cooled to 0° C. HBTU (0.50 g,1.3 mmol) and N,N-diisopropylethylamine (1.0 mL, 5.7 mmol) were added.The mixture was stirred for 20 minutes.2-amino-2-methyl-N-(2-pyrrolidin-1-ylethyl) propionamide dihydrochloride(0.38 g, 1.4 mmol) was added to the mixture. The resulting mixture wasstirred overnight. The mixture was added with water (60 mL) andextracted with ethyl acetate (100 mL×3). The combined organic phaseswere washed with saturated brine (100 mL), dried over anhydrous sodiumsulfate, filtered by suction, concentrated, and the residue was purifiedto silica gel column chromatography [dichloromethane/anhydrous methanol(v/v)=30/1] to give the title compound (0.99 g, colorless oil) in 99%yield.

Step 25:2-Methyl-2-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-0-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyrylamino]-N-(2-pyrrolidin-1-ylethyl)propionamide

2-Methyl-2-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyrylamino]-N-(2-pyrrolidin-1-ylethyl)propionamide(0.90 g, 0.96 mmol) was dissolved in anisole (30 mL) at roomtemperature, then the mixture was cooled to 0° C., and anhydrousaluminum trichloride (1.3 g, 9.7 mmol) was slowly added. The mixture wasstirred for 5 minutes, then warmed to room temperature and stirred for 3hours. The mixture was poured into ice water (50 mL), extracted withethyl acetate (30 mL×6), and the combined organic phases were washedsuccessively with saturated sodium bicarbonate solution (100 mL) andsaturated brine (100 mL), dried over anhydrous sodium sulfate, filteredby suction, concentrated, and the residue was purified by silica gelcolumn chromatography [dichloromethane/anhydrous methanol (v/v)=7/1] toobtain the title compound (0.28 g, white solid) in 44% yield.

MS (ESI, pos. ion) m/z: 668.5[M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.65 (br.s, 1H), 8.40 (s, 1H), 7.89(t, 1H), 7.29 (s, 1H), 7.23 (d, 1H), 7.12-7.04 (m, 5H), 5.50 (d, 1H),5.32 (t, 1H), 5.02 (d, 1H), 4.89 (d, 1H), 4.21 (s, 1H), 4.03 (d, 1H),3.91 (s, 2H), 3.81 (d, 1H), 3.72 (d, 1H), 3.50 (m, 2H), 3.19 (m, 2H),3.02 (s, 2H), 2.18 (s, 3H), 2.13 (t, 2H), 2.04-1.95 (m, 4H), 1.88-1.69(m, 4H), 1.29 (s, 6H), 1.21 (s, 3H), 1.15 (s, 3H).

Example 2N-[3-(2-Methylaminoethylamino)-3-oxo-propyl]-4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butanamide

Step 1: 3-(Benzyloxycarbonylamino)propionic acid

3-Aminopropionic acid (3.0 g, 34 mmol) was dissolved in dioxane (20 mL)at room temperature, then sodium carbonate (11.0 g, 104 mmol) and water(60 mL) were added. The mixture was cooled to 0° C., then benzylchloroformate (6.0 mL, 41 mmol) was added. The resulting mixture waswarmed to room temperature and stirred overnight. The mixture was washedwith n-hexane (100 mL), the aqueous phase was adjusted to pH=1 withdilute hydrochloric acid (1 M), extracted with ethyl acetate (100 mL×2),and the combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered by suction andconcentrated to obtain the title compound (6.9 g, colorless oil) in 92%yield.

Step 2: N-[3-(2-Dimethylaminoethylamino)-3-oxo-propyl]carbamic acidbenzyl ester

3-(Benzyloxycarbonylamino)propionic acid (3.0 g, 13 mmol) was dissolvedin dichloromethane (30 mL) at room temperature, and the mixture wascooled to 0° C. Then HATU (5.9 g, 15 mmol) and N,N-diisopropylethylamine(7.0 mL, 40 mmol) were added. The mixture was stirred for 20 minutes.N,N-Dimethyl-1,2-ethylenediamine (1.5 g, 17 mmol) was added, and theresulting mixture was warmed to room temperature and stirred overnight.The mixture was washed with water (20 mL), the organic phases wereconcentrated in vacuo, and the residue was purified by silica gel columnchromatography [dichloromethane/anhydrous methanol (v/v)=30/1] to givethe title compound (2.0 g, yellow oil) in 51% yield.

Step 3: 3-Amino-N-(2-dimethylaminoethyl)propanamide

To a mixed solution of benzylN-[3-(2-dimethylaminoethylamino)-3-oxo-propyl] carbamate (2.0 g, 6.0mmol) in tetrahydrofuran (2 mL) and anhydrous methanol (20 mL) was added10% palladium/carbon (0.20 g, 0.19 mmol) at room temperature, and themixture was stirred overnight under a hydrogen atmosphere. The mixturewas filtered with suction and concentrated to give the title compound(1.1 g, yellow oil) in 99% yield.

Step 4: 3-Amino-N-(2-dimethylaminoethyl) propionamide dihydrochloride

To a solution of 3-amino-N-(2-dimethylaminoethyl) propionamide (1.1 g,6.9 mmol) in ethyl acetate (20 mL) was added HCl isopropanol solution (4mL, 5 M) at room temperature, and the mixture was stirred for 1 hour.The mixture was filtered with suction, the filter cake was washed withethyl acetate (20 mL), and dried in vacuo to give the title compound(1.2 g, white solid) in 75% yield.

MS (ESI, pos. ion) m/z: 160.2[M+H]⁺.

¹H NMR (400 MHz, D₂O) δ (ppm): 3.56 (t, 2H), 3.24 (dt, 4H), 2.88 (s,6H), 2.67 (t, 2H).

Step 5:4-[4-[[2-Methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyricacid

To a mixed solution of4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyricacid (1.3 g, 1.7 mmol) in tetrahydrofuran (2 mL) and anhydrous methanol(20 mL) was added 10% palladium hydroxide/carbon (1.2 g, 0.84 mmol) atroom temperature, and the mixture was stirred overnight under a hydrogenatmosphere. The mixture was filtered by suction and concentrated, andthe residue was purified by silica gel column chromatography [ethylacetate] to obtain the title compound (0.52 g, white solid) in 53%yield.

Step 6:4-[4-[[2-Methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-triacetoxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyricacid

4-[4-[[2-Methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyric acid (0.40g, 0.82 mmol) was dissolved in tetrahydrofuran (10 mL) at roomtemperature, and the mixture was cooled to 10° C.4-dimethylaminopyridine (5 mg, 0.04 mmol), acetic anhydride (0.70 mL,7.5 mmol) and triethylamine (1.0 mL, 7.2 mmol) were added and theresulting mixture was stirred for 3 hours. The mixture was added withdilute hydrochloric acid (1 M) to adjust to pH=3, and extracted withethyl acetate (60 mL×3). The combined organic phases were washed withsaturated brine (80 mL), dried over anhydrous sodium sulfate, filteredby suction, concentrated, and the residue was purified by silica gelcolumn chromatography [ethyl acetate/petroleum ether (v/v)=1/1] toobtain the title compound (0.35 g, white solid) in 69% yield.

MS (ESI, pos. ion) m/z: 635.5 [M+Na]⁺.

Step 7:[(1S,2S,3S,4R,5S)-2,4-Diacetoxy-5-[3-[[4-[4-[[3-(2-methylaminoethylamino)-3-oxo-propyl]amino]-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate

4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-triacetoxy-1-(1-hydroxy-1-methyl-ethyl)-6,7,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyricacid (0.15 g, 0.25 mmol) was dissolved in dichloromethane (5 mL) at roomtemperature. The mixture was cooled to 0° C., then HATU (0.12 g, 0.29mmol) and N,N-diisopropylethylamine (0.22 mL, 1.3 mmol) were added. Theresulting mixture was stirred for 20 minutes.3-amino-N-(2-dimethylaminoethyl) propionamide dihydrochloride (74 mg,0.32 mmol) was added, and the mixture was stirred overnight. The mixturewas added with water (20 mL) and extracted with dichloromethane (40mL×3). The combined organic phases were washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered by suction,concentrated, and the residue was purified by silica gel columnchromatography [dichloromethane/anhydrous methanol (v/v)=8/1] to obtainthe title compound (0.11 g, white solid) in 60% yield.

MS (ESI, pos. ion) m/z: 754.6[M+H]⁺.

Step 8: N-[3-(2-Methylaminoethylamino)-3-oxo-propyl]-4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butanamide

To a solution of[(1S,2S,3S,4R,5S)-2,4-diacetoxy-5-[3-[[4-[4-[[3-(2-methylaminoethylamino)-3-oxo-propyl]amino]-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate(0.11 g, 0.15 mmol) in anhydrous methanol (2 mL) was added sodiummethoxide solid (41 mg, 0.75 mmol) at room temperature, and the mixturewas stirred for 2 hours. The mixture was concentrated, and the residuewas directly purified by preparative TLC [DCM/MeOH (v/v)=2/1] to givethe title compound (60 mg, white solid) in 65% yield.

MS (ESI, pos. ion) m/z: 628.3[M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.09 (s, 1H), 7.89 (t, 1H), 7.29 (s,1H), 7.23 (d, 1H), 7.11-7.03 (m, 5H), 5.50 (d, 1H), 5.32 (t, 1H), 5.02(d, 1H), 4.89 (d, 1H), 4.21 (s, 1H), 4.03 (d, 1H), 3.91 (s, 2H), 3.81(d, 1H), 3.72 (d, 1H), 3.47 (m, 2H), 3.24 (m, 2H), 2.90 (m, 2H), 2.60(s, 6H), 2.45 (t, 2H), 2.26 (t, 2H), 2.18 (s, 3H), 2.02 (t, 2H), 1.75(m, 2H), 1.21 (s, 3H), 1.15 (s, 3H).

Example 3N-(2-Diethylaminoethyl)-2-methyl-2-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyrylamino]propionamide

Step 1: BenzylN-[2-(2-diethylaminoethylamino)-1,1-dimethyl-2-oxo-ethyl]carbamate

2-(Benzyloxycarbonylamino)-2-methyl-propionic acid (3.0 g, 13 mmol) wasdissolved in dichloromethane (30 mL) at room temperature. The mixturewas cooled to 0° C., and HATU (5.6 g, 14 mmol) andN,N-diisopropylethylamine (7.0 mL, 40 mmol) were added. The resultingmixture was stirred for 20 minutes. N,N-Diethyl-1,2-ethylenediamine (1.9g, 16 mmol) was added and the mixture was stirred overnight. The mixturewas washed with water (20 mL), dried over anhydrous sodium sulfate,filtered by suction, concentrated, and the residue was purified bysilica gel column chromatography [dichloromethane/anhydrous methanol(v/v)=30/1] to give the title compound (3.8 g, yellow oil) in 90% yield.

MS (ESI, pos. ion) m/z: 336.4[M+H]⁺.

Step 2: 2-Amino-N-(2-diethylaminoethyl)-2-methyl-propionamide

To a solution of benzylN-[2-(2-diethylaminoethylamino)-1,1-dimethyl-2-oxo-ethyl] carbamate (1.0g, 3.0 mmol) in anhydrous methanol (20 mL) was added 10%palladium/carbon catalyst (0.20 g, 0.18 mmol) at room temperature, andthe mixture was stirred for 5 hours under a hydrogen atmosphere. Themixture was filtered with suction and concentrated in vacuo to give thetitle compound (0.6 g, yellow oil) in 99% yield.

Step 3: 2-Amino-N-(2-diethylaminoethyl)-2-methyl-propionamidedihydrochloride

To a solution of 2-amino-N-(2-diethylaminoethyl)-2-methyl-propionamide(0.50 g, 2.5 mmol) in ethyl acetate (20 mL) was added HCl isopropanolsolution (2 mL, 5 M) at room temperature, and the mixture was stirredfor 1 hour. The mixture was filtered with suction, the filter cake waswashed with ethyl acetate (20 mL), and dried in vacuo to give the titlecompound (0.6 g, white solid) in 90% yield.

MS (ESI, pos. ion) m/z: 202.4 [M+H]⁺.

Step 4:[(1S,2S,3S,4R,5S)-2,4-Diacetoxy-5-[3-[[4-[4-[[2-(2-diethylaminoethylamino)-1,1-dimethyl-2-oxoethyl]amino]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate

4-[4-[[2-Methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-triacetoxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyricacid (0.15 g, 0.25 mmol) was dissolved in methyl chloride (5 mL) at roomtemperature, then the mixture was cooled to 0° C. HATU (0.12 g, 0.29mmol) and N,N-diisopropylethylamine (0.22 mL, 1.3 mmol) were added andthe mixture was stirred for 20 minutes.2-Amino-N-(2-diethylaminoethyl)-2-methyl-propionamide dihydrochloride(88 mg, 0.32 mmol) was added and the mixture was stirred overnight. Themixture was added with water (20 mL) and extracted with dichloromethane(40 mL×3). The combined organic phases were washed with saturated brine(20 mL), dried over anhydrous sodium sulfate, filtered by suction,concentrated, and the residue was purified by silica gel columnchromatography [dichloromethane/anhydrous methanol (v/v)=8/1] to givethe title compound (90 mg, white solid) in 46% yield.

MS (ESI, pos. ion) m/z: 796.3 [M+H]⁺.

Step 5:N-(2-Diethylaminoethyl)-2-methyl-2-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyrylamino]propionamide

To a solution of[(1S,2S,3S,4R,5S)-2,4-diacetoxy-5-[3-[[4-[4-[[2-(2-diethylaminoethylamino)-1,1-dimethyl-2-oxoethyl]amino]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate(90 mg, 0.11 mmol) in anhydrous methanol (2 mL) was added solid sodiummethoxide (30 mg, 0.55 mmol), and the mixture was stirred for 2 hours.The mixture was concentrated, and the residue was directly purified bythin layer chromatography [DCM/MeOH (v/v)=2/1] to give the titlecompound (60 mg, white solid) in 79% yield.

MS (ESI, pos. ion) m/z: 670.3 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.02 (br.s, 1H), 08.23 (s, 1H), 7.93(t, 1H), 7.29 (s, 1H), 7.23 (d, 1H), 7.17-6.99 (m, 5H), 5.53 (d, 1H),5.04 (d, 1H), 4.89 (d, 1H), 4.21 (s, 1H), 4.04 (d, 1H), 3.91 (s, 2H),3.81 (d, 1H), 3.72 (m, 1H), 3.53-3.36 (m, 5H), 3.11 (t, 2H), 3.05 (m,4H), 2.18 (s, 3H), 2.13 (t, 2H), 1.75 (m, 2H), 1.29 (s, 6H), 1.24 (s,3H), 1.21 (s, 3H), 1.16 (s, 6H).

Example 4N-(2-Dimethylaminoethyl)-3-methyl-3-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyrylamino]butanamide

Step 1: 3(benzyloxycarbonylamino)-3-methyl-butyric acid

3-Amino-3-methyl-butyric acid (3.0 g, 26 mmol) was dissolved in dioxane(20 mL) at room temperature, then sodium carbonate (8.1 g, 76 mmol) andwater (60 mL) were added. The mixture was cooled to 0° C., then benzylchloroformate (4.5 mL, 30 mmol) was added. The resulting mixture waswarmed to room temperature and stirred overnight. The mixture was washedwith n-hexane (100 mL), the aqueous phases were adjusted to pH=1 withdilute hydrochloric acid (1 M), extracted with ethyl acetate (100 mL×2),and the combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered by suction, andconcentrated to obtain the title compound (5.4 g, colorless oil) in 84%yield.

Step 2:N-[3-(2-Dimethylaminoethylamino)-1,1-dimethyl-3-oxo-propyl]carbamic acidbenzyl ester

3-(Benzyloxycarbonylamino)-3-methyl-butyric acid (3.0 g, 12 mmol) wasdissolved in dichloromethane (30 mL) at room temperature, and themixture was cooled to 0° C. Then HATU (5.3 g, 13 mmol) andN,N-diisopropylethylamine (7.0 mL, 40 mmol) were added, and the mixturewas stirred for 20 minutes. N,N-dimethyl-1,2-ethylenediamine (1.4 g, 16mmol) was added, and the resulting mixture was warmed to roomtemperature and stirred overnight. The mixture was washed with water (20mL), the organic phases were concentrated in vacuo, and the residue waspurified by silica gel column chromatography [dichloromethane/anhydrousmethanol (v/v)=30/1] to give the title compound (3.0 g, yellow oil) in78% yield.

Step 3: 3-Amino-N-(2-dimethylaminoethyl)-3-methyl-butanamide

To a solution of benzylN-[3-(2-dimethylaminoethylamino)-1,1-dimethyl-3-oxo-propyl] carbamate(3.0 g, 9.3 mmol) in anhydrous methanol (30 mL) was added 10%palladium/carbon (0.30 g, 0.28 mmol) at room temperature, and themixture was stirred overnight under a hydrogen atmosphere. The mixturewas filtered with suction and concentrated in vacuo to give the titlecompound (1.7 g, yellow oil) in 97% yield.

Step 4: 3-Amino-N-(2-dimethyl aminoethyl)-3-methyl-butanamidedihydrochloride

To a solution of 3-amino-N-(2-dimethylaminoethyl)-3-methyl-butanamide(1.7 g, 9.1 mmol) in ethyl acetate (20 mL) was added HCl isopropanolsolution (5 mL, 5 M) at room temperature, and the mixture was stirredfor 1 hour. The mixture was filtered with suction, the filter cake waswashed with ethyl acetate (20 mL), and dried in vacuo to give the titlecompound (2.0 g, white solid) in 85% yield.

MS (ESI, pos. ion) m/z: 188.2 [M+H]⁺.

¹H NMR (400 MHz, D₂O) δ (ppm): 3.53 (t, J=6.2 Hz, 2H), 3.24 (t, J=6.1Hz, 2H), 2.84 (s, 6H), 2.55 (s, 2H), 1.32 (s, 6H).

Step 5:[(1S,2S,3S,4R,5S)-2,4-diacetoxy-5-[3-[[4-[4-[[3-(2-methylaminoethylamino)-1,1-dimethyl-3-oxo-propyl]amino]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate

4-[4-[[2-Methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-triacetoxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyricacid (0.15 g, 0.25 mmol) was dissolved in dichloromethane (5 mL) at roomtemperature, then the mixture was cooled to 0° C. HATU (0.12 g, 0.29mmol) and N,N-diisopropylethylamine (0.22 mL, 1.3 mmol) were added andthe mixture was stirred for 20 minutes.3-Amino-N-(2-dimethylaminoethyl)-3-methyl-butanamide dihydrochloride (83mg, 0.32 mmol) was added and the mixture was stirred overnight. Themixture was added with water (20 mL) and extracted with dichloromethane(40 mL×3). The combined organic phases were washed with saturated brine(20 mL), dried over anhydrous sodium sulfate, filtered by suction,concentrated, and the residue was purified by silica gel columnchromatography [dichloromethane/anhydrous methanol (v/v)=8/1] to obtainthe title compound (0.12 g, white solid) in 63% yield.

MS (ESI, pos. ion) m/z: 782.7[M+H]⁺.

Step 6:N-(2-Dimethylaminoethyl)-3-methyl-3-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyrylamino]butanamide

To a solution of [(IS,2S,3S,4R,5S)-2,4-diacetoxy-5-[3-[[4-[4-[[3-(2-methylaminoethylamino)-1,1-dimethyl-3-oxo-propyl]amino]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate(0.12 g, 0.15 mmol) in anhydrous methanol (2 mL) was added solid sodiummethoxide (41 mg, 0.75 mmol) at room temperature, and the mixture wasstirred for 2 hours. The mixture was concentrated, and the residue wasdirectly purified by TLC preparation [DCM/MeOH (v/v)=2/1] to give thetitle compound (60 mg, white solid) in 59% yield.

MS (ESI, pos. ion) m/z: 656.3[M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.07 (br.s, 1H), 7.71 (t, 1H), 7.49(s, 1H), 7.29 (s, 1H), 7.23 (d, 1H), 7.11-7.03 (m, 5H), 5.51 (d, 1H),5.02 (d, 1H), 4.88 (d, 1H), 4.21 (s, 1H), 4.03 (d, 1H), 3.90 (s, 2H),3.81 (d, 1H), 3.72 (d, 1H), 3.47-3.36 (m, 5H), 3.15 (m, 2H), 2.45 (s,2H), 2.24 (s, 6H), 2.18 (s, 3H), 2.02 (t, 2H), 1.73 (m, 2H), 1.29 (s,6H), 1.21 (s, 3H), 1.15 (s, 3H).

Example 5N-[3-(dimethylamino)propyl]-2-methyl-2-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyrylamino]propionamide

Step 1: benzylN-[2-[3-(Dimethylamino)propylamino]-1,1-dimethyl-2-oxo-ethyl]carbamate

2-(Benzyloxycarbonylamino)-2-methyl-propionic acid (3.0 g, 13 mmol) wasdissolved in dichloromethane (30 mL) at room temperature. The mixturewas cooled to 0° C., and HATU (5.6 g, 14 mmol) andN,N-diisopropylethylamine (7.0 mL, 40 mmol) were added. The resultingmixture was stirred for 20 minutes. N,N-Dimethyl-1,3-propanediamine (1.7g, 17 mmol) was added and the mixture was stirred overnight. The mixturewas washed with water (20 mL), dried over anhydrous sodium sulfate,filtered by suction, concentrated, and the residue was purified bysilica gel column chromatography [dichloromethane/anhydrous methanol(v/v)=30/1] to give the title compound (4.0 g, yellow oil) in 98% yield.

Step 2: 2-Amino-N-[3-(dimethylamino)propyl]-2-methyl-propionamide

To a solution of benzylN-[2-[3-(dimethylamino)propylamino]-1,1-dimethyl-2-oxo-ethyl] carbamate(4.0 g, 12 mmol) in anhydrous methanol (30 mL) was added 10%palladium/carbon (0.30 g, 0.28 mmol) at room temperature, and themixture was stirred overnight under a hydrogen atmosphere. The mixturewas filtered with suction and concentrated in vacuo to give the titlecompound (2.3 g, yellow oil) in 99% yield.

Step 3: 2-Amino-N-[3-(dimethylamino)propyl]-2-methyl-propionamidedihydrochloride

To a solution of2-amino-N-[3-(dimethylamino)propyl]-2-methyl-propionamide (2.3 g, 12mmol) in ethyl acetate (20 mL) was added HCl isopropanol solution (8 mL,5 M) at room temperature, and the mixture was stirred for 1 hour. Themixture was filtered with suction, the filter cake was washed with ethylacetate (20 mL), and dried in vacuo to give the title compound (2.5 g,white solid) in 78% yield.

MS (ESI, pos. ion) m/z: 188.2 [M+H]⁺.

Step 4:[(1S,2S,3S,4R,5S)-2,4-diacetoxy-5-[3-[[4-[4-[[2-[3-(dimethylamino)propyl]-1,1-dimethyl-2-oxo-ethyl]amino]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate

4-[4-[[2-Methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-triacetoxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyricacid (0.10 g, 0.16 mmol) was dissolved in dichloromethane (5 mL) at roomtemperature, then the mixture was cooled to 0° C. HATU (80 mg, 0.21mmol) and N,N-diisopropylethylamine (0.20 mL, 1.1 mmol) were added andthe mixture was stirred for 20 minutes.2-Amino-N-[3-(dimethylamino)propyl]-2-methyl-propionamidedihydrochloride (60 mg, 0.23 mmol) was added, and the mixture was warmedto room temperature and stirred overnight. The mixture was added withwater (20 mL) and extracted with dichloromethane (40 mL×3). The combinedorganic phases were washed with saturated brine (20 mL), dried overanhydrous sodium sulfate, filtered by suction, concentrated, and theresidue was purified by silica gel column chromatography[dichloromethane/anhydrous methanol (v/v)=8/1] to give the titlecompound (90 mg, white solid) in 80% yield.

MS (ESI, pos. ion) m/z: 782.6[M+H]⁺.

Step 5:N-[3-(Dimethylamino)propyl]-2-methyl-2-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyrylamino]propionamide

To a solution of(1S,2S,3S,4R,5S)-2,4-diacetoxy-5-[3-[[4-[4-[[2-[3-(dimethylamino)propyl]-1,1-dimethyl-2-oxo-ethyl]amino]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate(90 mg, 0.11 mmol) in anhydrous methanol (2 mL) was added solid sodiummethoxide (30 mg, 0.55 mmol) at room temperature, and the mixture wasstirred for 2 hours. The mixture was concentrated, and the residue wasdirectly purified by thin layer chromatography [DCM/MeOH (v/v)=2/1] togive the title compound (50 mg, white solid) in 66% yield.

MS (ESI, pos. ion) m/z: 656.3 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.95 (s, 1H), 7.70 (t, 1H), 7.29 (s,1H), 7.23 (d, 1H), 7.12-7.04 (m, 5H), 5.53 (d, 1H), 5.04 (d, 1H), 4.89(d, 1H), 4.21 (s, 1H), 4.04 (d, 1H), 3.91 (s, 2H), 3.81 (d, 1H), 3.73(t, 1H), 3.54-3.38 (m, 4H), 3.09 (m, 2H), 2.90 (m, 2H), 2.61 (s, 6H),2.18 (s, 3H), 2.11 (t, 2H), 1.78-1.67 (m, 4H), 1.29 (s, 6H), 1.21 (s,3H), 1.16 (s, 3H).

Example 6N-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl]-2-methyl-2-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octane-5-yl]phenyl]methyl]phenyl]butyrylamino]propionamide

Step 1: tert-Butyl N-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl]carbamate

(3R)-3-Fluoropyrrolidine hydrochloride (4.1 g, 33 mmol) was dissolved indimethylsulfoxide (40 mL) at room temperature, and tert-butylN-(2-bromoethyl)carbamate (6.9 g, 31 mmol) and N,N-diisopropylethylamine(11 mL, 64 mmol) were added. The resulting mixture was heated to 40° C.and stirred overnight. The mixture was added with water (150 mL) andextracted with ethyl acetate (100 mL×3). The combined organic phaseswere washed with saturated brine (50 mL), dried over anhydrous sodiumsulfate, filtered by suction, concentrated, and the residue was purifiedby silica gel column chromatography [ethyl acetate/petroleum ether(v/v)=1/1] to obtain the title compound (3.0 g, yellow oil) in 42%yield.

Step 2: 2-[(3R)-3-fluoropyrrolidin-1-yl]ethylamine

To a solution of tert-butylN-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl]carbamate (3.5 g, 15 mmol) inethyl acetate (30 mL) was added HCl ethyl acetate solution (10 mL, 4M)at room temperature, and the mixture was stirred for 2 hours. Themixture was concentrated, and the residue was dissolved in methanol (30mL). To the mixture was added solid sodium bicarbonate to adjust topH=8-9. The mixture was filtered by suction, and concentrated to obtainthe title compound (1.5 g, yellow oil) in 75% yield.

Step 3: BenzylN-[2-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethylamino]-1,1-dimethyl-2-oxo-ethyl]carbamate

2-(Benzyloxycarbonylamino)-2-methyl-propionic acid (1.0 g, 4.2 mmol) wasdissolved in dichloromethane (10 mL) at room temperature, and themixture was cooled to 0° C. HATU (1.9 g, 4.7 mmol) andN,N-diisopropylethylamine (2.2 mL, 13 mmol) were added, and theresulting mixture was stirred for 20 minutes.2-[(3R)-3-Fluoropyrrolidin-1-yl]ethylamine (0.7 g, 5.3 mmol) was addedand the mixture was stirred overnight. The mixture was washed with water(20 mL), dried over anhydrous sodium sulfate, filtered by suction,concentrated, and the residue was purified by silica gel columnchromatography [dichloromethane/anhydrous methanol (v/v)=30/1] to obtainthe title compound (1.1 g, colorless oil) in 74% yield.

MS (ESI, pos. ion) m/z: 352.1[M+H]⁺.

Step 4:2-Amino-N-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl]-2-methyl-propionamide

To a solution of benzylN-[2-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethylamino]-1,1-dimethyl-2-oxo-ethyl]carbamate(1.1 g, 3.1 mmol) in anhydrous methanol (30 mL) was added 10%palladium/carbon (0.20 g, 0.21 mmol) at room temperature, and themixture was stirred overnight under a hydrogen atmosphere. The mixturewas filtered with suction and concentrated in vacuo to give the titlecompound (0.68 g, yellow oil) in 99% yield.

Step 5:2-Amino-N-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl]-2-methyl-propionamidedihydrochloride

To a solution of2-amino-N-[3-(dimethylamino)propyl]-2-methyl-propionamide (0.68 g, 3.1mmol) in ethyl acetate (5 mL) was added HCl ethyl acetate solution (3mL, 4 M) at room temperature, and the mixture was stirred for 1 hour.The mixture was filtered with suction, and the filter cake was washedwith ethyl acetate (5 mL) and dried in vacuo to give the title compound(0.77 g, light yellow solid) in 85% yield.

MS (ESI, pos. ion) m/z: 218.1[M+H]⁺.

Step 6:[(1S,2S,3S,4R,5S)-2,4-diacetoxy-5-[3-[[4-[4-[[2-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethylamino]-1,1-dimethyl-2-oxo-ethyl]amino]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate

4-[4-[[2-Methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-triacetoxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyricacid (0.15 g, 0.25 mmol) was dissolved in methyl chloride (5 mL) at roomtemperature, then the mixture was cooled to 0° C. HATU (0.18 g, 0.47mmol) and N,N-diisopropylethylamine (0.22 mL, 1.3 mmol) were added andthe mixture was stirred for 20 minutes.2-Amino-N-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl]-2-methyl-propionamidedihydrochloride (93 mg, 0.32 mmol) was added, and the mixture wasstirred overnight. The mixture was added with water (20 mL) andextracted with dichloromethane (40 mL×3). The combined organic phaseswere washed with saturated brine (20 mL), dried over anhydrous sodiumsulfate, filtered by suction, concentrated, and the residue was purifiedby silica gel column chromatography [dichloromethane/anhydrous methanol(v/v)=20/1] to obtain the title compound (0.15 g, white solid) in 75%yield.

MS (ESI, pos. ion) m/z: 812.7[M+H]⁺.

Step 7:N-[2-[(3R)-3-Fluoropyrrolidin-1-yl]ethyl]-2-methyl-2-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octane-5-yl]phenyl]methyl]phenyl]butyrylamino]propionamide

To a solution of[(1S,2S,3S,4R,5S)-2,4-diacetoxy-5-[3-[[4-[4-[[2-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethylamino]-1,1-dimethyl-2-oxo-ethyl]amino]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate(0.15 g, 0.18 mmol) in anhydrous methanol (2 mL) was added solid sodiummethoxide (49 mg, 0.90 mmol) at room temperature, and the mixture wasstirred for 2 hours. The mixture was concentrated and the residue wasdirectly purified by TLC preparation [DCM/MeOH (v/v)=3/1] to give thetitle compound (100 mg, white solid) in 66% yield.

MS (ESI, pos. ion) m/z: 686.3[M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.20 (br.s, 1H), 7.77 (br.s, 1H),7.29 (s, 1H), 7.23 (d, 1H), 7.12-7.02 (m, 5H), 5.50 (d, 1H), 5.01 (d,1H), 4.87 (d, 1H), 4.20 (s, 1H), 4.04 (d, 1H), 3.91 (s, 2H), 3.81 (d,1H), 3.73 (t, 1H), 3.50-3.38 (m, 4H), 2.18 (s, 3H), 2.11 (t, 2H), 1.99(m, 1H), 1.75 (m, 2H), 1.29 (s, 6H), 1.21 (s, 3H), 1.16 (s, 3H).

Example 7N-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl]-1-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octane-5-yl]phenyl]methyl]phenyl]butyrylamino]cyclohexylformamide

Step 1: 1-(benzyloxycarbonylamino)cyclohexanecarboxylic acid

1-Aminocyclohexanecarboxylic acid (5.4 g, 38 mmol) was dissolved indioxane (30 mL) at room temperature, then sodium carbonate (11.0 g, 104mmol) and water (100 mL) were added. The resulting mixture was cooled to0° C., then benzyl chloroformate (6.0 mL, 41 mmol) was added. Themixture was warmed to room temperature and stirred overnight. Themixture was washed with n-hexane (100 mL), the aqueous phases wereadjusted to pH=2 with dilute hydrochloric acid (1 M), extracted withethyl acetate (100 mL×2), and the combined organic phases were washedwith saturated brine (100 mL), dried over anhydrous sodium sulfate,filtered by suction and concentrated to obtain the title compound (5.2g, colorless oil) in 50% yield.

Step 2: BenzylN-[1-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethylcarbamoyl]cyclohexyl]carbamate

1-(benzyloxycarbonylamino)cyclohexanecarboxylic acid (1.3 g, 4.7 mmol)was dissolved in dichloromethane (15 mL) at room temperature, then themixture was cooled to 0° C. HATU (2.0 g, 5.0 mmol) andN,N-diisopropylethylamine (2.3 mL, 13 mmol) were added, and theresulting mixture was stirred for 20 minutes.2-[(3R)-3-Fluoropyrrolidin-1-yl]ethylamine (0.70 g, 5.3 mmol) was added,and the mixture was warmed to room temperature and stirred overnight.The mixture was washed with water (20 mL), the organic phases wereconcentrated, and the residue was purified by silica gel columnchromatography [dichloromethane/anhydrous methanol (v/v)=30/1] to givethe title compound (1.6 g, colorless oil) in 87% yield.

MS (ESI, pos. ion) m/z: 392.2 [M+H]⁺.

Step 3: 1-amino-N-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl]cyclohexanecarboxamide

To a solution of benzylN-[1-[2-[(3R)-3-Fluoropyrrolidin-1-yl]ethylcarbamoyl]cyclohexyl]carbamate (1.6 g, 4.1 mmol) in anhydrous methanol (20 mL) wasadded 10% palladium/carbon catalyst (0.20 g, 0.19 mmol) at roomtemperature, and the mixture was stirred overnight under a hydrogenatmosphere. The mixture was filtered with suction and concentrated invacuo to give the title compound (1.1 g, yellow oil) in 99% yield.

Step 4: 1-Amino-N-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl]cyclohexanecarboxamide dihydrochloride

To a solution of1-amino-N-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl]cyclohexane carboxamide(1.0 g, 3.9 mmol) in ethyl acetate (5 mL) was added HCl ethyl acetatesolution (3 mL, 4 M) at room temperature, and the mixture was stirredfor 1 hour. The mixture was filtered with suction, the filter cake waswashed with ethyl acetate (5 mL), and dried in vacuo to give the titlecompound (1.1 g, white solid) in 86% yield.

MS (ESI, pos. ion) m/z: 258.1 [M+H]⁺.

Step 5:[(1S,2S,3S,4R,5S)-2,4-Diacetoxy-5-[3-[[4-[4-[[1-[2-[(3R)-3-fluoropyrrolidine-1-yl]ethylcarbamoyl]cyclohexyl]amino]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate

4-[4-[[2-Methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-triacetoxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyricacid (0.15 g, 0.25 mmol) was dissolved in dichloromethane (5 mL) at roomtemperature, then the mixture was cooled to 0° C. HATU (0.12 g, 0.32mmol) and N,N-diisopropylethylamine (0.22 mL, 1.3 mmol) were added andthe mixture was stirred for 20 minutes.1-amino-N-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl] cyclohexanecarboxamide dihydrochloride (110 mg, 0.32 mmol) was added, and themixture was warmed to room temperature and stirred overnight. Themixture was added with water (10 mL) and extracted with dichloromethane(40 mL×3). The combined organic phases were washed with saturated brine(20 mL), dried over anhydrous sodium sulfate, filtered with suction,concentrated, and the residue was purified by silica gel columnchromatography [dichloromethane/anhydrous methanol (v/v)=20/1] to obtainthe title compound (0.18 g, white solid) in 86% yield.

MS (ESI, pos. ion) m/z: 852.7 [M+H]⁺.

Step 6:N-[2-[(3R)-3-Fluoropyrrolidin-1-yl]ethyl]-1-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyrylamino] cyclohexyl formamide

To a solution of[(1S,2S,3S,4R,5S)-2,4-diacetoxy-5-[3-[[4-[4-[[1-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethylcarbamoyl]cyclohexyl]amino]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate (0.18 g, 0.21 mmol) in anhydrousmethanol (2 mL) was added solid sodium methoxide (57 mg, 1.05 mmol) atroom temperature, and the mixture was stirred for 2 hours. The mixturewas concentrated, and the residue was directly purified by thin layerchromatography preparation [DCM/MeOH (v/v)=3/1] to give the titlecompound 7 (90 mg, white solid) in 58% yield.

MS (ESI, pos. ion) m/z: 726.3 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.92 (br.s, 1H), 7.77 (br.s, 1H),7.30 (s, 1H), 7.23 (d, 1H), 7.12-7.03 (m, 5H), 5.50 (d, 1H), 5.01 (d,1H), 4.88 (d, 1H), 4.20 (s, 1H), 4.04 (d, 1H), 3.91 (s, 2H), 3.81 (d,1H), 3.72 (t, 1H), 3.53-3.38 (m, 6H), 2.23-2.15 (m, 5H), 1.99 (m, 1H),1.85 (d, 2H), 1.76 (m, 2H), 1.64 (m, 2H), 1.48 (m, 5H), 1.21 (s, 3H),1.16 (s, 3H).

Example 8N-(2-dimethylaminoethyl)-2-methyl-2-[methyl-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyryl]amino]propionamide

Step 1: tert-ButylN-[2-(2-dimethylaminoethylamino)-1,1,-dimethyl-2-oxo-ethyl]-N-methyl-formate

2-[-tert-Butoxycarbonyl(methyl)amino]-2-methylpropionic acid (2.6 g, 12mmol) was dissolved in dichloromethane (40 mL) at room temperature, andthe mixture was cooled to 0° C. HATU (5.8 g, 15 mmol) andN,N-diisopropylethylamine (6.3 mL, 36 mmol) were added, and theresulting mixture was stirred for 20 minutes.N,N-Dimethyl-1,2-ethylenediamine (1.6 g, 18 mmol) was added, and theresulting mixture was warmed to room temperature and stirred overnight.The resulting mixture was washed with water (30 mL), dried overanhydrous sodium sulfate, and filtered with suction. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (DCM/anhydrous MeOH (v/v)=20/1) to give the titlecompound (2.0 g, yellow oil) in 58% yield.

MS (ESI, pos. ion) m/z: 288.1 [M+H]⁺.

Step 2: N-(2-Dimethylaminoethyl)-2-methyl-2-(methylamino)propionamidedihydrochloride

To a solution of tert-butylN-[2-(2-dimethylaminoethylamino)-1,1,-dimethyl-2-oxo-ethyl]-N-methyl-formate(2.0 g, 7.0 mmol) in ethyl acetate (20 mL) was added HCl isopropanolsolution (4 mL, 5M) at room temperature, and the resulting mixture wasstirred overnight, cooled to 0° C. and stirred for 30 minutes. Themixture was filtered by suction, and the filter cake was washed withethyl acetate (5 mL) and dried in vacuo to obtain the title compound(1.3 g, yellow solid) in 71% yield.

Step 3:[(1S,2S,3S,4R,5S)-2,4-Diacetoxy-5-[3-[[4-[4-[[2-(2-dimethylaminoethylamino)-1,1-dimethyl-2-oxo-ethyl]methyl-amino]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate

4-[4-[[2-Methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-triacetoxy-1-(1-hydroxy-1-methyl-ethyl)-6,7,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyricacid (0.20 g, 0.33 mmol) was dissolved in dichloromethane (5 mL) at roomtemperature. The mixture was cooled to 0° C., then HATU (0.16 g, 0.40mmol) and N,N-diisopropylethylamine (0.30 mL, 1.7 mmol) were added. Theresulting mixture was stirred for 20 minutes.N-(2-Dimethylaminoethyl)-2-methyl-2-(methylamino)propionamidedihydrochloride (0.17 g, 0.66 mmol) was added, and the mixture wasstirred overnight. The mixture was added with water (20 mL) andextracted with dichloromethane (40 mL×3). The combined organic phaseswere washed with saturated brine (20 mL), dried over anhydrous sodiumsulfate, filtered with suction, concentrated, and the residue waspurified by silica gel column chromatography [dichloromethane/anhydrousmethanol (v/v)=8/1] to obtain the title compound (0.11 g, white solid)in 43% yield.

MS (ESI, pos. ion) m/z: 782.3[M+H]⁺.

Step 4:N-(2-dimethylaminoethyl)-2-methyl-2-[methyl-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyryl]amino]propionamide

To a solution of[(1S,2S,3S,4R,5S)-2,4-diacetoxy-5-[3-[[4-[4-[[2-(2-dimethylaminoethylamino)-1,1-dimethyl-2-oxo-ethyl]-methyl-amino]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate(0.11 g, 0.14 mmol) in anhydrous methanol (3 mL) was added solid sodiummethoxide (38 mg, 0.70 mmol) at room temperature, and the mixture wasstirred for 2 hours. The mixture was concentrated, and the residue wasdirectly purified by preparative TLC [DCM/MeOH (v/v)=4/1] to give thetitle compound (55 mg, white solid) in 61% yield.

MS (ESI, pos. ion) m/z: 656.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.71 (br.s, 1H), 7.85 (t, 1H), 7.30(s, 1H), 7.23 (d, 1H), 7.12-7.04 (m, 5H), 5.50 (d, 1H), 5.01 (d, 1H),4.88 (d, 1H), 4.20 (s, 1H), 4.04 (d, 1H), 3.91 (s, 2H), 3.81 (d, 1H),3.75-3.69 (m, 1H), 3.45-3.35 (m, 5H), 3.18 (s, 3H), 3.10 (t, 2H), 2.81(s, 6H), 2.18 (s, 3H), 2.12 (t, 2H), 1.75 (m, 2H), 1.29 (s, 6H), 1.21(s, 3H), 1.16 (s, 3H).

Example 9N-(2-Dimethylaminoethyl)-N,2-dimethyl-2-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyryl]propionamide

Step 1: tert-ButylN-[2-[2-dimethylaminoethyl(methyl)amino]-1,1,-dimethyl-2-oxo-ethyl]-formate

2-[-tert-Butoxycarbonyl(methyl)amino]-2-methylpropionic acid (2.0 g, 10mmol) was dissolved in dichloromethane (30 mL) at room temperature, andthe mixture was cooled to 0° C. HATU (4.7 g, 12 mmol) andN,N-diisopropylethylamine (5.2 mL, 30 mmol) were added, and theresulting mixture was stirred for 20 minutes.N,N′,N′-Trimethyl-1,2-ethylenediamine (1.5 g, 15 mmol) was added, andthe mixture was warmed to room temperature and stirred overnight. Theresulting mixture was washed with water (30 mL), dried over anhydroussodium sulfate, and filtered with suction. The filtrate was concentratedin vacuo and the residue was purified by silica gel columnchromatography (DCM/anhydrous MeOH (v/v)=20/1) to give the titlecompound (1.6 g, yellow oil) in 56% yield.

MS (ESI, pos. ion) m/z: 288.0 [M+H]⁺.

Step 2: 2-Amino-N-(2-dimethylaminoethyl)-N,2-dimethyl-propionamidedihydrochloride

To a solution of tert-butylN-[2-[2-dimethylaminoethyl(methyl)amino]-1,1,-dimethyl-2-oxo-ethyl]-carboxylate(1.6 g, 5.6 mmol) in ethyl acetate (20 mL) was added HCl isopropanolsolution (4 mL, 5M). The mixture was stirred overnight, cooled to 0° C.and stirred for 30 minutes. The mixture was filtered with suction, andthe filter cake was washed with ethyl acetate (5 mL) and dried in vacuoto obtain the title compound (1.0 g, yellow solid) in 69% yield.

Step 3: [(1S,2S,3S,4R,5S)-2,4-Diacetoxy-5-[3-[[4-[4-[[2-[2-dimethylaminoethyl(methyl)amino]-1,1-dimethyl-2-oxo-ethyl]-amino]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate

4-[4-[[2-Methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-triacetoxy-1-(1-hydroxy-1-methyl-ethyl)-6,7,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyricacid (0.20 g, 0.33 mmol) was dissolved in dichloromethane (5 mL) at roomtemperature. The mixture was cooled to 0° C., then HATU (0.16 g, 0.40mmol) and N,N-diisopropylethylamine (0.30 mL, 1.7 mmol) were added. Theresulting mixture was stirred for 20 minutes.2-Amino-N-(2-dimethylaminoethyl)-N,2-dimethyl-propionamidedihydrochloride (0.17 g, 0.66 mmol) was added and the mixture wasstirred overnight. The mixture was added with water (20 mL) andextracted with dichloromethane (40 mL×3). The combined organic phaseswere washed with saturated brine (20 mL), dried over anhydrous sodiumsulfate, filtered by suction, concentrated, and the residue was purifiedby silica gel column chromatography [dichloromethane/anhydrous methanol(v/v)=8/1] to obtain the title compound (0.13 g, white solid) in 50%yield.

MS (ESI, pos. ion) m/z: 782.2[M+H]⁺.

Step 4N-(2-Dimethylaminoethyl)-N,2-dimethyl-2-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyryl]propionamide

To a solution of[(1S,2S,3S,4R,5S)-2,4-diacetoxy-5-[3-[[4-[4-[[2-[2-dimethylaminoethyl(methyl)amino]-1,1-dimethyl-2-oxo-ethyl]-amino]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate (0.13 g, 0.17 mmol) in anhydrous methanol (3 mL) was added solidsodium methoxide (46 mg, 0.85 mmol) at room temperature, and the mixturewas stirred for 2 hours. The mixture was concentrated, and the residuewas directly purified by TLC preparation [DCM/MeOH (v/v)=4/1] to givethe title compound (42 mg, white solid) in 38% yield.

MS (ESI, pos. ion) m/z: 656.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.65 (br.s, 1H), 8.02 (s, 1H), 7.31(s, 1H), 7.24 (d, 1H), 7.12-7.04 (m, 5H), 5.49 (d, 1H), 5.00 (d, 1H),4.85 (d, 1H), 4.20 (s, 1H), 4.04 (d, 1H), 3.90 (s, 2H), 3.81 (d, 1H),3.73-3.69 (m, 1H), 3.44-3.35 (m, 5H), 3.10 (s, 3H), 3.06 (t, 2H), 2.80(s, 6H), 2.16 (s, 3H), 2.12 (t, 2H), 1.72 (m, 2H), 1.28 (s, 6H), 1.21(s, 3H), 1.16 (s, 3H).

Example 10(2S)—N-(2-dimethylaminoethyl)-1-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyryl]azetidine-2-carboxamide

Step 1: tert-Butyl(2S)-2-(2-dimethylaminoethylcarbamoyl)azetidine-1-formate

(2S)-1-tert-butoxycarbonylazetidine-2-carboxylic acid (3.0 g, 15 mmol)was dissolved in dichloromethane (50 mL) at room temperature, and themixture was cooled to 0° C. HATU (7.1 g, 18 mmol) andN,N-diisopropylethylamine (7.9 mL, 45 mmol) were added, and theresulting mixture was stirred for 20 minutes.N,N-Dimethyl-1,2-ethylenediamine (2.0 g, 23 mmol) was added, and theresulting mixture was warmed to room temperature and stirred overnight.The resulting mixture was washed with water (30 mL), dried overanhydrous sodium sulfate, and filtered with suction. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (DCM/anhydrous MeOH (v/v)=20/1) to give the titlecompound (2.6 g, yellow oil) in 64% yield.

MS (ESI, pos. ion) m/z: 272.0 [M+H]⁺.

Step 2: (2S)—N-(2-Dimethylaminoethyl)azetidine-2-carboxamidedihydrochloride

To a solution of tert-butyl(2S)-2-(2-dimethylaminoethylcarbamoyl)azetidine-1-formate (2.6 g, 9.6mmol) in ethyl acetate (20 mL) was added HCl isopropanol solution (6 mL,5M) at room temperature, and the mixture was stirred overnight, cooledto 0° C. and stirred for 30 minutes. The mixture was filtered bysuction, and the filter cake was washed with ethyl acetate (10 mL) anddried in vacuo to obtain the title compound (1.7 g, yellow solid) in 72%yield.

Step 3: [(1S,2S,3S,4R,5S)-2,4-Diacetoxy-5-[3-[[4-[(2S)-2-(2-dimethylaminoethylcarbamoyl)azetidine-1-yl]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate

4-[4-[[2-Methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-triacetoxy-1-(1-hydroxy-1-methyl-ethyl)-6,7,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyricacid (0.20 g, 0.33 mmol) was dissolved in dichloromethane (5 mL) at roomtemperature. The mixture was cooled to 0° C., then HATU (0.16 g, 0.40mmol) and N,N-diisopropylethylamine (0.30 mL, 1.7 mmol) were added. Theresulting mixture was stirred for 20 minutes.(2S)—N-(2-Dimethylaminoethyl)azetidine-2-carboxamide dihydrochloride(0.16 g, 0.66 mmol) was added, and the resulting mixture was stirredovernight. The mixture was added with water (20 mL) and extracted withdichloromethane (40 mL×3). The combined organic phases were washed withsaturated brine (20 mL), dried over anhydrous sodium sulfate, filteredby suction, concentrated, and the residue was purified by silica gelcolumn chromatography [dichloromethane/anhydrous methanol (v/v)=8/1] toobtain the title compound (0.18 g, white solid) in 71% yield.

MS (ESI, pos. ion) m/z: 766.2[M+H]⁺.

Step 4:(2S)—N-(2-Dimethylaminoethyl)-1-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyryl]azetidine-2-carboxamide

To a solution of[(1S,2S,3S,4R,5S)-2,4-diacetoxy-5-[3-[[4-[(2S)-2-(2-dimethylaminoethylcarbamoyl)azetidin-1-yl]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate (0.18 g, 0.23 mmol) in anhydrous methanol (5 mL) was added solidsodium methoxide (65 mg, 1.2 mmol) at room temperature, and the mixturewas stirred for 2 hours. The mixture was concentrated, and the residuewas directly purified by preparative TLC [DCM/MeOH (v/v)=4/1] to givethe title compound (0.10 g, white solid) in 68% yield.

MS (ESI, pos. ion) m/z: 640.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.21 (br.s, 1H), 8.18 (s, 1H), 7.29(s, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.13-7.02 (m, 5H), 5.55 (d, J=4.9 Hz,1H), 5.07 (d, J=5.4 Hz, 1H), 4.93 (d, J=6.8 Hz, 1H), 4.24 (s, 1H),4.20-4.15 (m, 1H), 4.03 (d, J=7.4 Hz, 1H), 3.92 (s, 2H), 3.82 (d, J=7.1Hz, 1H), 3.75-3.68 (m, 1H), 3.54-3.37 (m, 4H), 3.06 (s, 2H), 2.76 (d,J=21.9 Hz, 6H), 2.60-2.52 (m, 2H), 2.39-2.26 (m, 2H), 2.18 (s, 3H),2.07-1.95 (m, 2H), 1.88 (m, 1H), 1.77-1.72 (m, 2H), 1.21 (s, 3H), 1.15(s, 3H).

Example 11(2S)—N-(2-Dimethylaminoethyl)-1-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyryl]pyrrolidine-2-carboxamide

Step 1: benzyl(2S)-2-(2-dimethylaminoethylcarbamoyl)pyrrolidine-1-formate

(2S)-1-Benzyloxycarbonylpyrrolidine-2-carboxylic acid (4.0 g, 16 mmol)was dissolved in dichloromethane (50 mL) at room temperature, then themixture was cooled to 0° C. HATU (7.2 g, 19 mmol) andN,N-diisopropylethylamine (8.4 mL, 48 mmol) were added, and the mixturewas stirred for 20 minutes. N,N-Dimethyl-1,2-ethylenediamine (2.1 g, 24mmol) was added, and the resulting mixture was warmed to roomtemperature and stirred overnight. The resulting mixture was washed withwater (50 mL), dried over anhydrous sodium sulfate, and filtered withsuction. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (DCM/anhydrous MeOH(v/v)=30/1) to give the title compound (3.8 g, yellow oil) in 74% yield.

MS (ESI, pos. ion) m/z: 320.2 [M+H]⁺.

Step 2: (2S)—N-(2-Dimethylaminoethyl)pyrrolidine-2-carboxamide

To a reaction flask were added benzyl(2S)-2-(2-dimethylaminoethylcarbamoyl) pyrrolidine-1-formate (3.8 g, 12mmol), 10% palladium/carbon (0.50 g, 0.47 mmol), tetrahydrofuran (10 mL)and methanol (40 mL) at room temperature, and the mixture was stirredfor 2 hours under a hydrogen atmosphere. The mixture was filtered bysuction and concentrated to obtain the title compound (2.2 g, yellowoil) in 100% yield.

Step 3: (2S)—N-(2-Dimethylaminoethyl)pyrrolidine-2-carboxamidedihydrochloride

To a solution of (2S)—N-(2-dimethylaminoethyl)pyrrolidine-2-carboxamide(2.2 g, 12 mmol) in ethyl acetate (20 mL) was added HCl isopropanolsolution (6 mL, 5M) at room temperature, and the mixture was stirred for10 minutes, cooled to 0° C. and stirred for 30 minutes. The mixture wasfiltered by suction, and the filter cake was washed with ethyl acetate(20 mL) and dried in vacuo to obtain the title compound (2.8 g, yellowsolid) in 92% yield.

Step 4:[(1S,2S,3S,4R,5S)-2,4-Diacetoxy-5-[3-[[4-[(2S)-2-(2-dimethylaminoethylcarbamoyl)pyrrolidin-1-yl]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate

4-[4-[[2-Methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-triacetoxy-1-(1-hydroxy-1-methyl-ethyl)-6,7,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyricacid (0.20 g, 0.33 mmol) was dissolved in dichloromethane (5 mL) at roomtemperature. The mixture was cooled to 0° C., then HATU (0.16 g, 0.40mmol) and N,N-diisopropylethylamine (0.30 mL, 1.7 mmol) were added. Theresulting mixture was stirred for 20 minutes.(2S)—N-(2-Dimethylaminoethyl)pyrrolidine-2-carboxamide dihydrochloride(0.17 g, 0.66 mmol) was added, and the mixture was stirred overnight.The mixture was added with water (20 mL) and extracted withdichloromethane (40 mL×3). The combined organic phases were washed withsaturated brine (20 mL), dried over anhydrous sodium sulfate, filteredby suction, concentrated, and the residue was purified by silica gelcolumn chromatography [dichloromethane/anhydrous methanol (v/v)=8/1] toobtain the title compound (0.20 g, white solid) in 79% yield.

MS (ESI, pos. ion) m/z: 780.2[M+H]⁺.

Step 5:(2S)—N-(2-Dimethylaminoethyl)-1-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyryl]pyrrolidine-2-carboxamide

To a solution of[(1S,2S,3S,4R,5S)-2,4-diacetoxy-5-[3-[[4-[(2S)-2-(2-dimethylaminoethylcarbamoyl)pyrrolidin-1-yl]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate(0.20 g, 0.26 mmol) in anhydrous methanol (5 mL) was added solid sodiummethoxide (70 mg, 1.3 mmol) at room temperature, and the mixture wasstirred for 2 hours. The mixture was concentrated, and the residue wasdirectly purified by TLC preparation [DCM/MeOH (v/v)=4/1] to give thetitle compound (0.12 g, white solid) in 72% yield.

MS (ESI, pos. ion) m/z: 654.3[M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.80 (br.s, 1H), 8.17 (s, 1H), 7.28(s, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.12-7.02 (m, 5H), 5.55 (d, J=4.9 Hz,1H), 5.06 (d, J=5.4 Hz, 1H), 4.92 (d, J=6.8 Hz, 1H), 4.22 (s, 1H),4.20-4.14 (m, 1H), 4.03 (d, J=7.4 Hz, 1H), 3.91 (s, 2H), 3.81 (d, J=7.1Hz, 1H), 3.74-3.68 (m, 1H), 3.54-3.37 (m, 4H), 3.05 (s, 2H), 2.71 (d,J=21.9 Hz, 6H), 2.57-2.52 (m, 2H), 2.35-2.24 (m, 2H), 2.17 (s, 3H),2.07-1.95 (m, 2H), 1.90-1.81 (m, 2H), 1.80-1.71 (m, 3H), 1.21 (s, 3H),1.15 (s, 3H).

Example 12(2R)—N-(2-Dimethylaminoethyl)-1-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyryl]pyrrolidine-2-carboxamide

(2R)-1-Benzyloxycarbonylpyrrolidine-2-carboxylic acid instead of(2S)-1-benzyloxycarbonylpyrrolidine-2-carboxylic acid was used as thestarting material, referring to the method described in Example 11, thetitle compound was obtained as white solid.

MS (ESI, pos. ion) m/z: 654.3[M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.96 (br.s, 1H), 8.15 (s, 1H), 7.29(s, 1H), 7.22 (d, J=7.2 Hz, 1H), 7.17-6.96 (m, 5H), 5.55 (d, J=4.9 Hz,1H), 5.06 (d, J=4.8 Hz, 1H), 4.91 (d, J=6.3 Hz, 1H), 4.22 (s, 1H), 4.18(d, J=4.7 Hz, 1H), 4.03 (d, J=7.9 Hz, 1H), 3.91 (s, 2H), 3.81 (d, J=6.6Hz, 1H), 3.72 (m, 1H), 3.56-3.37 (m, 4H), 3.01 (s, 2H), 2.66 (d, J=31.6Hz, 6H), 2.58-2.52 (m, 2H), 2.32-2.23 (m, 2H), 2.17 (s, 3H), 2.06-1.93(s, 2H), 1.88-1.80 (m, 2H), 1.80-1.68 (m, 3H), 1.21 (s, 3H), 1.15 (s,3H).

Example 13(2S,4S)—N-(2-dimethylaminoethyl)-4-hydroxy-1-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyryl]pyrrolidine-2-carboxamide

Step 1: benzyl(2S,4S)-2-(2-dimethylaminoethylcarbamoyl)-4-hydroxy-pyrrolidine-1-formate

(2S,4R)-1-benzyloxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (5.0g, 19 mmol) was dissolved in dichloromethane (80 mL) at roomtemperature, then the mixture was cooled to 0° C. HATU (8.7 g, 23 mmol),N,N-diisopropylethylamine (10 mL, 57 mmol) andN,N-dimethyl-1,2-ethylenediamine (2.4 g, 27 mmol) were added in turn,and the resulting mixture was warmed to room temperature and stirredovernight. The resulting mixture was washed with water (50 mL), driedover anhydrous sodium sulfate, and filtered with suction. The filtratewas concentrated in vacuo and the residue was purified by silica gelcolumn chromatography (DCM/anhydrous MeOH (v/v)=15/1) to give the titlecompound (2.2 g, yellow oil) in 35% yield.

MS (ESI, pos. ion) m/z: 336.0 [M+H]⁺.

Step 2:(2S,4S)—N-(2-Dimethylaminoethyl)-4-hydroxy-pyrrolidine-2-carboxamide

To the reaction flask were added benzyl(2S,4S)-2-(2-dimethylaminoethylcarbamoyl)-4-hydroxy-pyrrolidine-1-formate(2.2 g, 6.6 mmol), 10% palladium/carbon (0.50 g, 0.47 mmol),tetrahydrofuran (10 mL) and methanol (40 mL) at room temperature, andthe mixture was stirred overnight under a hydrogen atmosphere. Themixture was filtered by suction and concentrated to obtain the titlecompound (1.3 g, yellow oil) in 100% yield.

Step 3:(2S,4S)—N-(2-Dimethylaminoethyl)-4-hydroxy-pyrrolidine-2-carboxamidedihydrochloride

To a solution of (2S,4S)—N-(2-dimethylaminoethyl)-4-hydroxy-pyrrolidine-2-carboxamide (1.3 g, 6.5 mmol) inethyl acetate (15 mL) was added HCl isopropanol solution (2 mL, 5M) atroom temperature, and the mixture was stirred for 30 minutes. Themixture was filtered by suction, and the filter cake was washed withethyl acetate (5 mL) and dried in vacuo to obtain the title compound(0.95 g, white solid) in 53% yield.

MS (ESI, pos. ion) m/z: 202.0 [M+H]⁺.

Step 4:[(1S,2S,3S,4R,5S)-2,4-Diacetoxy-5-[3-[[4-[4-[(2S,4S)-2-(2-dimethylaminoethylcarbamoyl)-4-hydroxy-pyrrolidin-1-yl]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]]acetate

4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-triacetoxy-1-(1-hydroxy-1-methyl-ethyl)-6,7,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyricacid (0.30 g, 0.49 mmol) was dissolved in dichloromethane (10 mL) atroom temperature, then the mixture was cooled to 0° C. HATU (0.28 g,0.74 mmol), N,N-diisopropylethylamine (0.50 mL, 2.9 mmol) and(2S,4S)—N-(2-dimethylaminoethyl)-4-hydroxy-pyrrolidine-2-carboxamidedihydrochloride (0.20 g, 0.74 mmol) were added in turn, and theresulting mixture was stirred overnight. The mixture was added withwater (20 mL) and extracted with dichloromethane (20 mL×3). The combinedorganic phases were washed with saturated brine (20 mL), dried overanhydrous sodium sulfate, filtered by suction, concentrated, and theresidue was purified by silica gel column chromatography[dichloromethane/anhydrous methanol (v/v)=7/1] to obtain the titlecompound (0.25 g, light yellow solid) in 64% yield.

MS (ESI, pos. ion) m/z: 796.2[M+H]⁺.

Step 5:(2S,4S)—N-(2-Dimethylaminoethyl)-4-hydroxy-1-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyryl]pyrrolidine-2-carboxamide

To a solution of[(1S,2S,3S,4R,5S)-2,4-diacetoxy-5-[3-[[4-[4-[(2S,4S)-2-(2-dimethylaminoethylcarbamoyl)-4-hydroxy-pyrrolidin-1-yl]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]]acetate (0.25 g, 0.31 mmol) in anhydrous methanol (8 mL) was added solidsodium methoxide (70 mg, 1.3 mmol) at room temperature. The mixture wasstirred for 2 hours. The mixture was concentrated, and the residue wasdirectly purified by preparative TLC [DCM/MeOH (v/v)=4/1] to give thetitle compound (0.12 g, white solid) in 58% yield.

MS (ESI, pos. ion) m/z: 670.2[M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.37 (br.s, 1H), 8.16 (s, 1H), 7.27(s, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.11-7.02 (m, 5H), 5.55 (d, J=4.9 Hz,1H), 5.05 (d, J=5.4 Hz, 1H), 4.92 (d, J=6.8 Hz, 1H), 4.35 (d, J=5.9 Hz,1H), 4.21 (s, 1H), 4.20-4.15 (m, 1H), 4.02 (d, J=7.4 Hz, 1H), 3.90 (s,2H), 3.80 (d, J=7.1 Hz, 1H), 3.76 (m, 1H), 3.73-3.68 (m, 1H), 3.54-3.38(m, 4H), 3.18 (m, 1H), 3.04 (s, 2H), 2.70 (d, J=21.9 Hz, 6H), 2.55-2.51(m, 2H), 2.38-2.25 (m, 3H), 2.17 (s, 3H), 2.10-1.98 (m, 2H), 1.71 (m,1H), 1.21 (s, 3H), 1.15 (s, 3H).

Example 14(2S,4R)—N-(2-Dimethylaminoethyl)-4-fluoro-1-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyryl]pyrrolidine-2-carboxamide

Step 1: (2S,4R)-1-Benzyloxycarbonyl-4-fluoro-pyrrolidine-2-carboxylicacid

(2S,4R)-4-Fluoro-pyrrolidine-2-carboxylic acid (3.0 g, 18 mmol) wasdissolved in 1,4-dioxane (20 mL) at room temperature, then water (60 mL)and sodium carbonate (7.5 g, 71 mmol) were added in turn. The mixturewas cooled to 0° C., and CbzCl (3.0 mL, 21 mmol) was added dropwise. Theresulting mixture was stirred at room temperature overnight. Thereaction was stopped, and the reaction solution was washed with n-hexane(100 mL). The aqueous phases were adjusted to pH=2 with 1 M dilutehydrochloric acid, extracted with ethyl acetate (100 mL), washed withsaturated sodium chloride solution (100 mL), dried over anhydrous sodiumsulfate, and concentrated in vacuo to obtain the title compound (4.7 g,colorless oil) in 99% yield.

Step 2: Benzyl(2S,4R)-2-(2-dimethylaminoethylcarbamoyl)-4-fluoro-pyrrolidine-1-formate

(2S,4R)-1-Benzyloxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid (4.7g, 18 mmol) was dissolved in dichloromethane (50 mL) at roomtemperature, then the mixture was cooled to 0° C. HATU (8.4 g, 22 mmol)and N,N-diisopropylethylamine (9.5 mL, 54 mmol) were added, and theresulting mixture was stirred for 20 minutes.N,N-Dimethyl-1,2-ethylenediamine (2.4 g, 27 mmol) was added, and theresulting mixture was warmed to room temperature and stirred overnight.The resulting mixture was washed with water (50 mL), dried overanhydrous sodium sulfate, and filtered with suction. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (DCM/anhydrous MeOH (v/v)=20/1) to give the titlecompound (3.0 g, yellow oil) in 51% yield.

MS (ESI, pos. ion) m/z: 338.0 [M+H]⁺.

Step 3:(2S,4R)—N-(2-Dimethylaminoethyl)-4-fluoro-pyrrolidine-2-carboxamide

To a reaction flask were added benzyl(2S,4R)-2-(2-dimethylaminoethylcarbamoyl)-4-fluoro-pyrrolidine-1-formate(3.0 g, 8.9 mmol), 10% palladium/carbon (0.50 g, 0.47 mmol),tetrahydrofuran (10 mL) and methanol (40 mL) at room temperature. Themixture was stirred overnight under a hydrogen atmosphere. The mixturewas filtered by suction and concentrated to obtain the title compound(1.8 g, yellow oil) in 100% yield.

Step 4: (2S,4R)—N-(2-Dimethylaminoethyl)-4-fluoro-pyrrolidine-2-carboxamide dihydrochloride

To a solution of(2S,4R)—N-(2-dimethylaminoethyl)-4-fluoro-pyrrolidine-2-carboxamide (1.8g, 8.9 mmol) in ethyl acetate (20 mL) was added HCl isopropanol solution(3 mL, 5M) at room temperature. The mixture was stirred for 30 minutes.The mixture was filtered by suction, and the filter cake was washed withethyl acetate (10 mL) and dried in vacuo to obtain the title compound(1.4 g, white solid) in 57% yield.

MS (ESI, pos. ion) m/z: 204.2 [M+H]⁺.

Step 5[(1S,2S,3S,4R,5S)-2,4-Diacetoxy-5-[3-[[4-[4-[(2S,4R)-2-(2-dimethylaminoethylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]]acetate

4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-triacetoxy-1-(1-hydroxy-1-methyl-ethyl)-6,7,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyricacid (0.33 g, 0.54 mmol) was dissolved in dichloromethane (10 mL) atroom temperature, then the mixture was cooled to 0° C. HATU (0.26 g,0.65 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.9 mmol) were added,and the mixture was stirred for 20 minutes.(2S,4R)—N-(2-Dimethylaminoethyl)-4-fluoro-pyrrolidine-2-carboxamidedihydrochloride (0.30 g, 1.1 mmol) was added and the mixture was stirredovernight. The mixture was added with water (20 mL) and extracted withdichloromethane (20 mL×3). The combined organic phases were washed withsaturated brine (20 mL), dried over anhydrous sodium sulfate, filteredby suction, concentrated, and the residue was purified by silica gelcolumn chromatography [dichloromethane/anhydrous methanol (v/v)=8/1] toobtain the title compound (0.32 g, light yellow solid) in 75% yield.

MS (ESI, pos. ion) m/z: 798.2[M+H]⁺.

Step 6:(2S,4R)—N-(2-dimethylaminoethyl)-4-fluoro-1-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyryl]pyrrolidine-2-carboxamide

To a solution of[(1S,2S,3S,4R,5S)-2,4-diacetoxy-5-[3-[[4-[4-[(2S,4R)-2-(2-dimethylaminoethylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]]acetate (0.32 g, 0.40 mmol) in anhydrous methanol (8 mL) was added solidsodium methoxide (0.11 g, 2.0 mmol) at room temperature. The mixture wasstirred for 2 hours. The mixture was concentrated, and the residue wasdirectly purified by preparative TLC [DCM/MeOH (v/v)=4/1] to give thetitle compound (0.17 g, white solid) in 63% yield.

MS (ESI, pos. ion) m/z: 672.3[M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.45 (br.s, 1H), 8.37 (t, J=5.5 Hz,1H), 7.29 (s, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.12-7.00 (m, 5H), 5.44 (s,0.5H), 5.30 (s, 0.5H), 5.56 (d, J=4.9 Hz, 1H), 5.08 (d, J=5.4 Hz, 1H),4.93 (d, J=6.8 Hz, 1H), 4.24 (s, 1H), 4.21-4.16 (m, 1H), 4.04 (d, J=7.4Hz, 1H), 3.92 (s, 2H), 3.83 (d, J=7.1 Hz, 1H), 3.76-3.69 (m, 1H),3.56-3.38 (m, 4H), 3.07 (s, 2H), 2.77 (d, J=21.9 Hz, 6H), 2.36-2.18 (m,3H), 2.35-2.24 (m, 2H), 2.17 (s, 3H), 2.14-1.94 (m, 2H), 1.76 (m, 2H),1.21 (s, 3H), 1.15 (s, 3H).

Example 15(2S)—N-(2-dimethylaminoethyl)-1-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyryl]piperidine-2-carboxamide

Step 1: tert-Butyl(2S)-2-(2-Dimethylaminoethylcarbamoyl)piperidine-1-formate

(2S)-1-tert-Butoxycarbonylpiperidine-2-carboxylic acid (3.7 g, 16 mmol)was dissolved in dichloromethane (50 mL) at room temperature, then themixture was cooled to 0° C. HATU (7.2 g, 19 mmol) andN,N-diisopropylethylamine (8.4 mL, 48 mmol) was added and the resultingmixture was stirred for 20 minutes. N,N-Dimethyl-1,2-ethylenediamine(2.1 g, 24 mmol) was added, and the resulting mixture was warmed to roomtemperature and stirred overnight. The resulting mixture was washed withwater (30 mL), dried over anhydrous sodium sulfate, and filtered withsuction. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (DCM/anhydrous MeOH(v/v)=20/1) to give the title compound (2.7 g, yellow oil) in 56% yield.

MS (ESI, pos. ion) m/z: 300.1 [M+H]⁺.

Step 2: (2S)—N-(2-Dimethylaminoethyl)piperidine-2-carboxamidedihydrochloride

To a solution of tert-butyl(2S)-2-(2-dimethylaminoethylcarbamoyl)piperidine-1-formate (2.7 g, 9.0mmol) in ethyl acetate (20 mL) was added HCl isopropanol solution (6 mL,5M) at room temperature. The mixture was stirred overnight, cooled to 0°C. and stirred for 30 minutes. The mixture was filtered by suction, andthe filter cake was washed with ethyl acetate (10 mL) and dried in vacuoto obtain the title compound (1.9 g, yellow solid) in 78% yield.

Step 3:[(1S,2S,3S,4R,5S)-2,4-Diacetoxy-5-[3-[[4-[(2S)-2-(2-dimethylaminoethylcarbamoyl)piperidin-1-yl]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate

4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-triacetoxy-1-(1-hydroxy-1-methyl-ethyl)-6,7,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyricacid (0.20 g, 0.33 mmol) was dissolved in dichloromethane (5 mL) at roomtemperature, then the mixture was cooled to 0° C. HATU (0.16 g, 0.40mmol) and N,N-diisopropylethylamine (0.30 mL, 1.7 mmol) were added, andthe mixture was stirred for 20 minutes.(2S)—N-(2-dimethylaminoethyl)piperidine-2-carboxamide dihydrochloride(0.18 g, 0.66 mmol) was added, and the mixture was stirred overnight.The mixture was added with water (20 mL) and extracted withdichloromethane (40 mL×3). The combined organic phases were washed withsaturated brine (20 mL), dried over anhydrous sodium sulfate, filteredby suction, concentrated, and the residue was purified by silica gelcolumn chromatography [dichloromethane/anhydrous methanol (v/v)=8/1] toobtain the title compound (0.14 g, white solid) in 53% yield.

MS (ESI, pos. ion) m/z: 794.3[M+H]⁺.

Step 4:(2S)—N-(2-Dimethylaminoethyl)-1-[4-[4-[[2-methyl-5-[(1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl]phenyl]methyl]phenyl]butyryl]piperidine-2-carboxamide

To a solution of[(1S,2S,3S,4R,5S)-2,4-diacetoxy-5-[3-[[4-[(2S)-2-(2-dimethylaminoethylcarbamoyl)piperidin-1-yl]-4-oxo-butyl]phenyl]methyl]-4-methyl-phenyl]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate (0.14 g, 0.18 mmol) in anhydrous methanol (5 mL) was added solidsodium methoxide (49 mg, 0.9 mmol) at room temperature. Then mixture wasstirred for 2 hours. The mixture was concentrated, and the residue wasdirectly purified by TLC preparation [DCM/MeOH (v/v)=4/1] to give thetitle compound (76 mg, white solid) in 63% yield.

MS (ESI, pos. ion) m/z: 668.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.65 (br.s, 1H), 8.17 (s, 1H), 7.28(s, 1H), 7.20 (d, J=7.8 Hz, 1H), 7.12-7.01 (m, 5H), 5.53 (d, J=4.9 Hz,1H), 5.06 (d, J=5.4 Hz, 1H), 4.91 (d, J=6.8 Hz, 1H), 4.23 (s, 1H),4.18-4.14 (m, 1H), 4.05 (d, J=7.3 Hz, 1H), 3.91 (s, 2H), 3.83 (d, J=7.0Hz, 1H), 3.76-3.67 (m, 1H), 3.55-3.39 (m, 4H), 3.07 (s, 2H), 2.77 (d,J=21.7 Hz, 6H), 2.63-2.55 (m, 2H), 2.40-2.28 (m, 2H), 2.17 (s, 3H),2.03-1.92 (m, 3H), 1.87-1.73 (m, 6H), 1.21 (s, 3H), 1.15 (s, 3H).

Test Example

1. Determination of SGLT1 Inhibitory Activity

Testing Purposes:

The following methods can be used to determine the inhibitory activityof the compounds described in the invention for SGLT1.

Test Materials:

¹⁴C-AMG solution was purchased from PerkinElmer, Cat. No. NEZ080001MC;

-   -   α-methylglucoside was purchased from Sigma, Cat. No. M9376-100G;

N-methyl-D-glucosamine was purchased from Sigma, Cat. No. M2004-100G;

phloridzin was purchased from Sigma, Cat. No. P3449-1G;

96-well plate was purchased from Corning, Cat. No. 3903.

Test Method:

Mock-transfected FIP-in CHO cells (3×10⁴ cells) and CHO cells expressinghuman SGLT1 gene were seeded into 96-well plates respectively. The cellswere incubated for 12 hours. Each well of the 96-well plates was washedwith 150 μL of sodium-free buffer once. To each well was added 50 μL ofsodium-containing buffer containing test compounds having differentconcentrations and 0.5 μm [¹⁴C]-AMG And the mixture in the well wasincubated at 37° C. for 1 hour. To each well was added 150 μL ofprecooled sodium-free buffer to terminate the reaction. The cell pelletwas washed with sodium free buffer three times and the residual liquidin well was removed. To each well was added 20 μL of precooled 100 mMNaOH, and the 96-well plates were vibrated at 900 rpm for 5 minutes.Scintillation fluid (80 μL) was added to each well which was thenvibrated at 600 rpm for 5 minutes. The amount of 14C-AMG wasquantitatively detected using liquid scintillation. The results wereshown in table 1:

TABLE 1 SGLT1 inhibitory activity of the compounds provided by theexamples of the present invention Example No. IC₅₀(SGLT1)/nM Example 11.73 Example 7 1.16 Example 11 5.75

The test results show that the compounds of the present invention have asignificant inhibitory effect on SGLT1.

2. Oral Glucose Tolerance Test and Glycosuria Excretion Test

Test Purpose:

The following methods were used to evaluate the effects of the compoundsof the invention in improving oral glucose tolerance and promotingglycosuria excretion.

Test Materials:

The glucose was purchased from Cheng Du Kelong Chemical Reagent Company.

Urine sugar test was determined on Roche biochemical analyzer.

Blood glucose test was determined on Roche Accu-Chek Performa BloodGlucose Meter.

Test Method 1:

The weight and the blood glucose levels of C57BL/6 mice were measuredafter an overnight 15-hour fast. The mice were grouped by their weightsand fasting plasma glucose levels. Each test group was administered withthe corresponding test compound at a dose of 1 mg/kg once by gavage, andthe blank control group was administered solvent. After 15 minutes, theblood glucose level (i.e., zero point blood glucose) of each group wasmeasured, and then each group was administered glucose (2.5 g/kg) onceimmediately by gavage. The blood was drawn from the caudal vein of theC57BL/6 mice at 15, 30, 60 and 120 minutes after glucose administrationand the blood glucose levels were measured continuously on blood-glucosemeter. The rate of decrease of the area under the blood glucose curve(AUC_(Glu 0-120) min) within 120 minutes after glucose administrationwas calculated.

After blood glucose level at 120 min time point was measured, each groupwas placed in a metabolism cage, and the urine was collected during 2.25hours to 6 hours and 6 hours to 24 hours after drug administration withthe metabolism cage as the unit. The urine volume of each metabolismcage at each time point was measured. The mice had free access to foodand water during the urine collection. After urine collection, thesupernatant was collected by centrifugation, and the urine glucoseconcentration of C57BL/6 mice at various time points was detected byRoche automatic biochemical analyzer.

Test Method 2:

The weight and the blood glucose levels of male SD rats were measuredafter an overnight 15-hour fast. The rats were grouped by their weightsand fasting plasma glucose levels. Each test group was administered withthe corresponding test compound at a dose of 1 mg/kg once by gavage, andthe blank control group was administered solvent. After 30 minutes, theblood glucose level (i.e., zero point blood glucose) of each group wasmeasured, and then each group was administered glucose (4.0 g/kg)immediately by gavage. The blood was drawn from the caudal vein of theSD rats at 15, 30 and 60 minutes after glucose administration and theblood glucose levels were measured continuously on blood-glucose meter.The rate of decrease of the area under the blood glucose curve(AUC_(Glu 0-60) min) within 60 minutes after glucose administration wascalculated.

After blood glucose level at 60 min time point was measured, each groupwas placed in a metabolism cage, and the urine was collected during 1.5hours to 24 hours and 24 hours to 48 hours after drug administrationwith the metabolism cage as the unit. The urine volume of eachmetabolism cage at each time point was measured. The mice had freeaccess to food and water during the urine collection. After urinecollection, the supernatant was collected by centrifugation, and theurine glucose concentration of the SD rats at various time points wasdetected by Roche automatic biochemical analyzer.

The test results show that the compounds of the present invention areeffective in reducing blood glucose levels.

The test results show that the compounds of the present invention have asignificant effect in promoting urine glucose excretion.

3. Pharmacokinetic Evaluation after Intravenous or Oral Quantificationof the Compounds of the Present Invention

Test Purpose:

The following test were used to evaluate the pharmacokinetic propertiesof the compounds of the present invention in animals.

Test Method:

The SD rats were weighted after an overnight 15-hour fast. The rats wererandomly grouped by their weights. The test compounds were dissolved in5% DMSO+5% Koliphor HS 15+90% saline vehicle for administration. For thetest group administered intravenously, the rats were given a dose of 1mg/kg, 2 mg/kg, or 5 mg/kg; for the test group administered orally, therats were given a dose of 5 mg/kg. Then, venous blood (approximately 0.2mL) was taken at 0.083 hours before and at 0.083 (intravenous grouponly), 0.25, 0.5, 1.0, 2.0, 5.0, 7.0, and 24 hours after administration,placed in an EDTAK₂ anticoagulation tube, and centrifuged at 11000 rpmfor 2 minutes. The plasma was collected and stored at 20° C. or 70° C.until LC/MS/MS analysis. The drug concentration in plasma was measuredat each time point. The WinNonlin 6.3 software non-compartment modelmethod was used to calculate the pharmacokinetic parameters, and thedrug time curve was drawn.

The test results show that the compounds provided by the presentinvention exhibit excellent pharmacokinetic properties when administeredintravenously or orally.

Reference throughout this specification to “an embodiment”, “someembodiments”, “one embodiment”, “another example”, “an example”, “aspecific example”, or “some examples” means that a particular feature,structure, material, or characteristic described in connection with theembodiment or example is included in at least one embodiment or exampleof the present disclosure. Thus, the appearances of the phrases such as“in some embodiments”, “in one embodiment”, “in an embodiment”, “inanother example”, “in an example”, “in a specific example”, or “in someexamples” in various places throughout this specification are notnecessarily referring to the same embodiment or example of the presentdisclosure. Furthermore, the particular features, structures, materials,or characteristics may be combined in any suitable manner in one or moreembodiments or examples. In addition, those skilled in the art canintegrate and combine different embodiments, examples or the features ofthem as long as they are not contradictory to one another.

Although explanatory embodiments have been shown and described, it wouldbe appreciated by those skilled in the art that the above embodimentscannot be construed to limit the present disclosure, and changes,alternatives, and modifications can be made in the embodiments withoutdeparting from spirit, principles and scope of the present disclosure.

The invention claimed is:
 1. A compound having Formula (I) or astereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, apharmaceutically acceptable salt, a dimer, or a trimer thereof,

wherein, L is —(CR^(a)R^(b))_(q)—, —CH═CH—(CR^(a)R^(b))_(p)—,—O—(CR^(a)R^(b))_(p)—, —NH—(CR^(a)R^(b))_(p)—, —S—(CR^(a)R^(b))_(p)—,—S(═O)—(CR^(a)R^(b))_(p)— or —S(═O)₂—(CR^(a)R^(b))_(p)—; q is 1, 2, 3,4, 5 or 6; p is 0, 1, 2, 3, 4, 5 or 6; each R^(a) and R^(b) isindependently H, D, F, Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆alkylamino, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl or 3-6 memberedheterocyclyl; or, R^(a) and R^(b) together with the carbon atom to whichthey are attached, form a C₃₋₆ carbocycle or a 3-6 membered heterocycle;R¹ is H, D, F, Cl, Br, I, OH, CN, NO₂, NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylthio, C₃₋₆ cycloalkyl or C₃₋₆cycloalkyl-C₁₋₄ alkylene, wherein each of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylthio, C₃₋₆ cycloalkyl and C₃₋₆cycloalkyl-C₁₋₄ alkylene is independently unsubstituted or substitutedwith 1, 2, 3 or 4 substituents, and the substituent is independentlyselected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino or C₁₋₆ haloalkoxy;each of R² and R³ is independently H, D, CN, OH, NH₂, —SH, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆alkylamino, C₃₋₆ cycloalkyl or 3-6 membered heterocyclyl, wherein eachC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio,C₁₋₆ alkylamino, C₃₋₆ cycloalkyl and 3-6 membered heterocyclyl isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, ═O, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino or C₁₋₆ haloalkoxy; or, R² andR³ together with the carbon atom to which they are attached, formcarbonyl, or, R² and R³ together with the carbon atom to which they areattached, form a C₃₋₆ carbocycle or a 3-6 membered heterocycle, whereineach of C₃₋₆ carbocycle and 3-6 membered heterocycle is independentlyunsubstituted or substituted with 1, 2, 3 or 4 substituents, and thesubstituent is independently selected from D, F, Cl, Br, I, CN, NO₂, OH,NH₂, —C(═O) OH, —SH, ═O, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆alkylamino or C₁₋₆ haloalkoxy; R⁴ is H, D, —OR^(4a) or —SR^(4b); each ofR^(4a) and R^(4b) is independently H, D, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₃₋₆ cycloalkyl-C₁₋₄ alkylene, 5-6 membered heterocyclyl, (5-6 memberedheterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5-6membered heteroaryl or (5-6 membered heteroaryl)-C₁₋₄ alkylene, whereineach C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, 5-6membered heterocyclyl, (5-6 membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5-6 membered heteroaryl and (5-6membered heteroaryl)-C₁₋₄ alkylene is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O)OH, —SH, ═O, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino orC₁₋₆ haloalkoxy; each R¹⁰ is independently H, D, F, Cl, Br, I, OH, CN,NO₂, NH₂, C₁₋₆ alkyl or C₁₋₆ alkoxy; R⁵ is H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl, C₆₋₁₀ aryl or 5-8membered heteroaryl, wherein each of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, 3-8 membered heterocyclyl, C₆₋₁₀ aryl and 5-8 memberedheteroaryl is independently unsubstituted or substituted with 1, 2, 3 or4 substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, ═O, —C(═O) OH, —C(═O) NH₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino,C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, 5-6 membered heterocyclyl, C₆₋₁₀ arylor 5-6 membered heteroaryl; each of R⁶ and R⁷ is independently H, D, F,Cl, Br, I, CN, NO₂, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₈ cycloalkyl, 3-8 memberedheterocyclyl, C₆₋₁₀ aryl or 5-8 membered heteroaryl, wherein each C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₃₋₈ cycloalkyl, 3-8 membered heterocyclyl, C₆₋₁₀ aryl and 5-8 memberedheteroaryl is independently unsubstituted or substituted with 1, 2, 3 or4 substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, ═O, —C(═O) OH, —C(═O) NH₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino,C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, 5-6 membered heterocyclyl, C₆₋₁₀ arylor 5-6 membered heteroaryl; or, R⁶ and R⁷ together with the carbon atomto which they are attached, form a C₃₋₈ carbocycle, a 3-8 memberedheterocycle, a C₆₋₁₀ aromatic ring or a 5-8 membered heteroaromaticring, wherein each of C₃₋₈ carbocycle, 3-8 membered heterocycle, C₆₋₁₀aromatic ring and 5-8 membered heteroaromatic ring is independentlyunsubstituted or substituted with 1, 2, 3 or 4 substituents, and thesubstituent is independently selected from D, F, Cl, Br, I, CN, NO₂, OH,NH₂, ═O, —C(═O) OH, —C(═O) NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino or C₁₋₆ haloalkoxy; or R⁵and R⁶ together with the atom to which they are attached, or R⁵ and R⁷together with the atom to which they are attached, form a 3-8 memberedheterocycle or a 5-8 membered heteroaromatic ring, wherein each 3-8membered heterocycle and 5-8 membered heteroaromatic ring isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, ═O, —C(═O) OH, —C(═O) NH₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino orC₁₋₆ haloalkoxy; each of R⁸ and R⁹ is independently H, D, R^(e)O—C₁₋₄alkylene, R^(d)R^(c)N—C₁₋₄ alkylene, C₁₋₈ alkyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₄ alkylene, 3-8 membered heterocyclyl,(3-8 membered heterocyclyl) —C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkylene, 5-8 membered heteroaryl or (5-8 membered heteroaryl)-C₁₋₄alkylene, wherein each C₁₋₈ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl,C₃₋₈cycloalkyl-C₁₋₄ alkylene, 3-8 membered heterocyclyl, (3-8 memberedheterocyclyl) —C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5-8membered heteroaryl and (5-8 membered heteroaryl)-C₁₋₄ alkylene isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, ═O, —OR^(e), —NR^(c)R^(d), —C(═O) OR^(e), —C(═O)NHR^(f), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ alkylamino or C₁₋₆ haloalkoxy; or, R⁸ and R⁹ together withthe nitrogen atom to which they are attached, form a 3-8 memberedheterocycle or a 5-8 membered heteroaromatic ring, wherein each of 3-8membered heterocycle and 5-8 membered heteroaromatic ring isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, ═O, —OR^(e), —NR^(c)R^(d), —C(═O)OR^(e),—C(═O)NHR^(f), C₁₋₆ alkyl, C₂₋₆ alkenyl, C²⁻⁶ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ alkylamino or C₁₋₆ haloalkoxy; each R^(c), R^(d),R^(e) and R^(f) is independently H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₄ alkylene, 3-8 membered heterocyclyl,(3-8 membered heterocyclyl) —C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkylene, 5-8 membered heteroaryl or (5-8 membered heteroaryl)-C₁₋₄alkylene, wherein each C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl,C₃₋₈cycloalkyl-C₁₋₄ alkylene, 3-8 membered heterocyclyl, (3-8 memberedheterocyclyl) —C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5-8membered heteroaryl and (5-8 membered heteroaryl)-C₁₋₄ alkylene isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, —NH₂, ═O, —C(═O)OH, —C(═O)NH₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino orC₁₋₆ haloalkoxy; or, R^(c) and R^(d) together with the nitrogen atom towhich they are attached, form a 3-8 membered heterocycle or a 5-8membered heteroaromatic ring, wherein each of 3-8 membered heterocycleand 5-8 membered heteroaromatic ring is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, ═O, OH, —NH₂,—C(═O)OH, —C(═O)NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C²⁻⁶ alkynyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino or C₁₋₆ haloalkoxy; n is 0, 1, 2or 3; t is 0, 1, 2, 3, 4, 5 or 6; with the proviso that when R⁵ and R⁸are both H, and R⁹ is

t is not
 0. 2. The compound of claim 1 having Formula (II):


3. The compound of claim 1, wherein R¹ is H, D, F, Cl, Br, I, OH, CN,NO₂, NH₂, methyl, ethyl, n-propyl, isopropyl, propenyl, propynyl,methoxy, ethoxy, hydroxymethyl, trifluoromethyl, trifluoroethyl,monofluoromethyl, trifluoromethoxy, difluoromethoxy, methylamino,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcyclopropyl-methylene, wherein each of methyl, ethyl, n-propyl,isopropyl, propenyl, propynyl, methoxy, ethoxy, hydroxymethyl,trifluoroethyl, monofluoromethyl, difluoromethoxy, methylamino,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcyclopropyl-methylene is independently unsubstituted or substituted with1, 2, 3, or 4 substituents, and the substituent is independentlyselected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, methyl,ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy,methylamino, trifluoromethoxy or difluoromethoxy.
 4. The compound ofclaim 1, wherein each of R² and R³ is independently H, D, CN, OH, NH₂,—SH, methyl, ethyl, n-propyl, isopropyl, vinyl, propynyl, methoxy,ethoxy, methylthio, methylamino, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or 5-6 membered heterocyclyl, wherein each methyl, ethyl,n-propyl, isopropyl, vinyl, propynyl, methoxy, ethoxy, methylthio,methylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 5-6membered heterocyclyl is independently unsubstituted or substituted with1, 2, 3 or 4 substituents, and the substituent is independently selectedfrom D, F, Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, ═O, methyl,ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethyloxy,methylamino, trifluoromethoxy or difluoromethoxy; or, R² and R³ togetherwith the carbon atom to which they are attached, form carbonyl, or, R²and R³ together with the carbon atom to which they are attached, formcyclopropane, cyclobutane, cyclopentane, cyclohexane or a 5-6 memberedheterocycle, wherein each of cyclopropane, cyclobutane, cyclopentane,cyclohexane and a 5-6 membered heterocycle is independentlyunsubstituted or substituted with 1, 2, 3 or 4 substituents, and thesubstituent is independently selected from D, F, Cl, Br, I, CN, NO₂, OH,NH₂, —C(═O) OH, —SH, ═O, methyl, ethyl, n-propyl, isopropyl,trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxy ordifluoromethoxy.
 5. The compound of claim 1, wherein R⁴ is H, D,—OR^(4a) or —SR^(4b); each of R^(4a) and R^(4b) is independently H, D,methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene,tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, (5-6 membered heterocyclyl)—C₁₋₂ alkylene, phenyl, phenyl-C₁₋₂ alkylene, furyl, pyrrolyl, pyridyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl,pyridazinyl, pyrimidinyl or (5-6 membered heteroaryl) —C₁₋₂ alkylene,wherein each methyl, ethyl, n-propyl, isopropyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene,tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, (5-6 membered heterocyclyl)—C₁₋₂ alkylene, phenyl, phenyl-C₁₋₂ alkylene, furyl, pyrrolyl, pyridyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl,pyridazinyl, pyrimidinyl and (5-6 membered heteroaryl) —C₁₋₂ alkylene isindependently unsubstituted or substituted with 1, 2, 3, or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, —C(═O) OH, —SH, ═O, methyl, ethyl,n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, methylamino,trifluoromethoxy or difluoromethoxy.
 6. The compound of claim 1, whereinR¹⁰ is H, D, F, Cl, Br, I, OH, CN, NO₂, NH₂, methyl, ethyl, n-propyl,isopropyl, methoxy or ethoxy.
 7. The compound of claim 1, wherein R⁵ isH, D, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, 5-6 memberedheterocyclyl, C₆₋₁₀ aryl or 5-6 membered heteroaryl, wherein each ofC₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, 5-6 membered heterocyclyl,C₆₋₁₀ aryl and 5-6 membered heteroaryl is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O,—C(═O) OH, —C(═O) NH₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₁₋₄ haloalkoxy, C₃₋₆cycloalkyl, 5-6 membered heterocyclyl, C₆₋₁₀ aryl or 5-6 memberedheteroaryl; each of R⁶ and R⁷ is independently H, D, F, Cl, Br, I, CN,NO₂, OH, NH₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, 5-6 membered heterocyclyl, C₆₋₁₀ arylor 5-6 membered heteroaryl, wherein each C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylamino, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, 5-6membered heterocyclyl, C₆₋₁₀ aryl and 5-6 membered heteroaryl isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, ═O, —C(═O) OH, —C(═O) NH₂, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, 5-6 membered heterocyclyl, C₆₋₁₀ arylor 5-6 membered heteroaryl; or, R⁶ and R⁷ together with the carbon atomto which they are attached, form a C₃₋₆ carbocycle, a 5-6 memberedheterocycle, a C₆₋₁₀ aromatic ring or a 5-6 membered heteroaromaticring, wherein each of C₃₋₆ carbocycle, 5-6 membered heterocycle, C₆₋₁₀aromatic ring and 5-6 membered heteroaromatic ring is independentlyunsubstituted or substituted with 1, 2, 3 or 4 substituents, and thesubstituent is independently selected from D, F, Cl, Br, I, CN, NO₂, OH,NH₂, ═O, —C(═O) OH, —C(═O) NH₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino or C₁₋₄ haloalkoxy; or R⁵and R⁶ together with the atom to which they are attached, or R⁵ and R⁷together with the atom to which they are attached, form a 3-6 memberedheterocycle or a 5-6 membered heterocycle, wherein each 3-6 memberedheterocycle and 5-6 membered heterocycle is independently unsubstitutedor substituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O,—C(═O) OH, —C(═O) NH₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino or C₁₋₄ haloalkoxy.
 8. Thecompound of claim 1, wherein R⁵ is H, D, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl,piperidinyl, morpholinyl, thiomorpholyl, piperazinyl, phenyl, furyl,pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl,pyridazinyl or pyrimidinyl, wherein each of methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl,piperidinyl, morpholinyl, thiomorpholyl, piperazinyl, phenyl, furyl,pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl,pyridazinyl and pyrimidinyl is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O,—C(═O) OH, —C(═O) NH₂, methyl, ethyl, n-propyl, isopropyl, vinyl,ethynyl, trifluoromethyl, methoxy, ethoxy, methylamino,trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentylor phenyl; each of R⁶ and R⁷ is independently H, D, F, Cl, Br, I, CN,NO₂, OH, NH₂, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, methoxy, ethoxy, methylamino, trifluoromethyl,trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl,1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl orpyrimidinyl, wherein each methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, methoxy, ethoxy, methylamino, difluoromethoxy,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholyl,piperazinyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl,thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, ═O, —C(═O) OH, —C(═O) NH₂, methyl, ethyl,n-propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, methoxy, ethoxy,methylamino, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl,cyclopentyl or phenyl; or, R⁶ and R⁷ together with the carbon atom towhich they are attached, form cyclopropane, cyclobutane, cyclopentane,cyclohexane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene,tetrahydropyran, tetrahydrothiopyran, piperidine, morpholine,thiomorpholine, piperazine, benzene ring, furan, pyrrole, pyridine,pyrazole, imidazole, triazole, tetrazole, oxazole, oxadiazole,1,3,5-triazine, thiazole, thiophene, pyrazine, pyridazine or pyrimidine,wherein each of cyclopropane, cyclobutane, cyclopentane, cyclohexane,pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran,tetrahydrothiopyran, piperidine, morpholine, thiomorpholine, piperazine,benzene ring, furan, pyrrole, pyridine, pyrazole, imidazole, triazole,tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole, thiophene,pyrazine, pyridazine and pyrimidine is independently unsubstituted orsubstituted with 1, 2, 3, or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O,—C(═O) OH, —C(═O) NH₂, methyl, ethyl, n-propyl, isopropyl, vinyl,ethynyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxyor difluoromethoxy; or R⁵ and R⁶ together with the atom to which theyare attached, or R⁵ and R⁷ together with the atom to which they areattached, form aziridine, azetidine, pyrrolidine, pyrazolidine,imidazolidine, oxazolidine, thiazolidine, piperidine, morpholine,thiomorpholine, piperazine, pyrrole, pyridine, pyrazole, imidazole,triazole, tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole,pyrazine, pyridazine or pyrimidine, wherein each aziridine, azetidine,pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, thiazolidine,piperidine, morpholine, thiomorpholine, piperazine, pyrrole, pyridine,pyrazole, imidazole, triazole, tetrazole, oxazole, oxadiazole,1,3,5-triazine, thiazole, pyrazine, pyridazine and pyrimidine isindependently unsubstituted or substituted with 1, 2, 3, or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, NH₂, ═O, —C(═O) OH, —C(═O) NH₂, methyl, ethyl,n-propyl, isopropyl, vinyl, ethynyl, trifluoromethyl, methoxy, ethoxy,methylamino, trifluoromethoxy or difluoromethoxy.
 9. The compound ofclaim 1, wherein each of R⁸ and R⁹ is independently H, D, R^(e)O—C₁₋₄alkylene, R^(d)R^(c)N—C₁₋₄ alkylene, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, 5-6 membered heterocyclyl,(5-6 membered heterocyclyl) —C₁₋₂ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₂alkylene, 5-6 membered heteroaryl or (5-6 membered heteroaryl)-C₁₋₂alkylene, wherein each of C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl,C₃₋₆cycloalkyl-C₁₋₂ alkylene, 5-6 membered heterocyclyl, (5-6 memberedheterocyclyl) —C₁₋₂ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₂ alkylene, 5-6membered heteroaryl and (5-6 membered heteroaryl)-C₁₋₂ alkylene isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, ═O, —OR^(e), —NR^(c)R^(d), —C(═O) OR^(e), —C(═O)NHR^(f), C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ alkylamino or C₁₋₄haloalkoxy; or, R⁸ and R⁹ together withthe nitrogen atom to which they are attached, form a 3-6 memberedheterocycle or a 5-6 membered heteroaromatic ring, wherein each of 3-6membered heterocycle and 5-6 membered heteroaromatic ring isindependently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, ═O, —OR^(e), —NR^(c)R^(d), —C(═O)OR^(e),—C(═O)NHR^(f), C₁₋₄ alkyl, C₂₋₄ alkenyl, C²⁻⁴ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy, C₁₋₄ alkylamino or C₁₋₄ haloalkoxy.
 10. The compound ofclaim 1, wherein each of R⁸ and R⁹ is independently H, D,R^(d)R^(c)N—C₁₋₄ alkylene, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl, n-hexyl, trifluoromethyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene,pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,thiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, (5-6 membered heterocyclyl) —C₁₋₂ alkylene, phenyl, C₆₋₁₀aryl-C₁₋₂ alkylene, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl,thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl or (5-6 memberedheteroaryl) —C₁₋₂ alkylene, wherein each methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C₃₋₆ cycloalkyl-C₁₋₂alkylene, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,thiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, (5-6 membered heterocyclyl) —C₁₋₂ alkylene, phenyl, C₆₋₁₀aryl-C₁₋₂ alkylene, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl,thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl and (5-6membered heteroaryl) —C₁₋₂ alkylene is independently unsubstituted orsubstituted with 1, 2, 3, or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, ═O, —OH,—NR^(c)R^(d), —C(═O)OH, —C(═O)NH₂, methyl, ethyl, n-propyl, vinyl,ethynyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxyor difluoromethoxy; or, R⁸ and R⁹ together with the nitrogen atom towhich they are attached, form aziridine, azetidine, pyrrolidine,pyrazolidine, imidazolidine, oxazolidine, thiazolidine, piperidine,morpholine, thiomorpholine, piperazine, pyrazole, imidazole, triazole,tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole, pyrazine,pyridazine or pyrimidine, wherein each of aziridine, azetidine,pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, thiazolidine,piperidine, morpholine, thiomorpholine, piperazine, pyrazole, imidazole,triazole, tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole,pyrazine, pyridazine and pyrimidine is independently unsubstituted orsubstituted with 1, 2, 3, or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, ═O, —OH,—NR^(c)R^(d), —C (═O) OH, —C(═O) NH₂, methyl, ethyl, n-propyl, vinyl,ethynyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxyor difluoromethoxy.
 11. The compound of claim 1, wherein each R^(e),R^(d), R^(e) and R^(f) is independently H, D, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, 5-6 memberedheterocyclyl, (5-6 membered heterocyclyl) —C₁₋₂ alkylene, C₆₋₁₀ aryl,C₆₋₁₀ aryl-C₁₋₂ alkylene, 5-6 membered heteroaryl or (5-6 memberedheteroaryl)-C₁₋₂ alkylene, wherein each C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, 5-6 membered heterocyclyl,(5-6 membered heterocyclyl) —C₁₋₂ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₂alkylene, 5-6 membered heteroaryl and (5-6 membered heteroaryl)-C₁₋₂alkylene is independently unsubstituted or substituted with 1, 2, 3 or 4substituents, and the substituent is independently selected from D, F,Cl, Br, I, CN, NO₂, OH, —NH₂, ═O, —C(═O)OH, —C(═O)NH₂, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino orC₁₋₄ haloalkoxy; or, R^(c) and R^(d) together with the nitrogen atom towhich they are attached, form a 3-6 membered heterocycle or a 5-6membered heteroaromatic ring, wherein each of 3-6 membered heterocycleand 5-6 membered heteroaromatic ring is independently unsubstituted orsubstituted with 1, 2, 3 or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, ═O, OH, —NH₂,—C(═O)OH, —C(═O)NH₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C²⁻⁴ alkynyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino or C₁₋₄ haloalkoxy.
 12. Thecompound of claim 1, wherein each R^(c), R^(d), R^(e) and R^(f) isindependently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene, pyrrolidinyl,pyrazolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, (5-6 membered heterocyclyl) —C₁₋₂ alkylene, phenyl,phenyl-C₁₋₂ alkylene, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl,thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl or (5-6 memberedheteroaryl) —C₁₋₂ alkylene, wherein each methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene, pyrrolidinyl,pyrazolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, (5-6 membered heterocyclyl) —C₁₋₂ alkylene, phenyl,phenyl-C₁₋₂ alkylene, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl,thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl and (5-6membered heteroaryl) —C₁₋₂ alkylene is independently unsubstituted orsubstituted with 1, 2, 3, or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, —NH₂, ═O,—C(═O) OH, —C(═O) NH₂, methyl, ethyl, n-propyl, isopropyl, vinyl,ethynyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxyor difluoromethoxy; or, R^(c) and R^(d) together with the nitrogen atomto which they are attached, form aziridine, azetidine, pyrrolidine,pyrazolidine, imidazolidine, oxazolidine, thiazolidine, piperidine,morpholine, thiomorpholine, piperazine, pyrazole, imidazole, triazole,tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole, pyrazine,pyridazine or pyrimidine, wherein each of aziridine, azetidine,pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, thiazolidine,piperidine, morpholine, thiomorpholine, piperazine, pyrazole, imidazole,triazole, tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole,pyrazine, pyridazine and pyrimidine is independently unsubstituted orsubstituted with 1, 2, 3, or 4 substituents, and the substituent isindependently selected from D, F, Cl, Br, I, CN, NO₂, OH, NH₂, ═O,—C(═O) OH, —C(═O) NH₂, methyl, ethyl, n-propyl, isopropyl, vinyl,ethynyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxyor difluoromethoxy.
 13. The compound of claim 1 having one of thefollowing structures:

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, asolvate, a pharmaceutically acceptable salt, a dimer, or a trimerthereof.
 14. A pharmaceutical composition comprising the compound ofclaim 1 and a pharmaceutically acceptable carrier, excipient, adjuvant,vehicle or a combination thereof.
 15. The pharmaceutical composition ofclaim 14 further comprising one or more other additional therapeuticagents, wherein the other additional therapeutic agent is selected froman anti-diabetic drug, an anti-hyperglycemic drug, an anti-obesity drug,an anti-hypertensive drug, an appetite suppressant drug, alipid-lowering drug, or a combination thereof.
 16. The pharmaceuticalcomposition of claim 15, wherein each anti-diabetic andanti-hyperglycemic drug is independently selected from a SGLT2inhibitor, a biguanide drug, a sulfonylurea drug, a glucosidaseinhibitor, a PPAR agonist, a αP2 inhibitor, PPARα/γ dual activator, adipeptidyl peptidase IV inhibitor, a glinides drug, an insulin, aglucagon-like peptide-1 inhibitor, a PTP1B inhibitor, a glycogenphosphorylase inhibitor, a glucose-6-phosphatase inhibitor or acombination thereof; wherein the anti-obesity drug is selected from acentral anti-obesity drug, a MCH receptor antagonist, a neuropeptide Yreceptor antagonist, a cannabinoid receptor antagonist, acerebrointestinal peptide antagonist, a lipase inhibitor, a (33 agonist,a 11β-HSD1 inhibitor, a DGAT-1 inhibitor, a peptide appetite inhibitor,a cholecystokinin agonist, a feeding inhibitor or a combination thereof;wherein the lipid-lowering drug is selected from a MTP inhibitor, aHMGCoA reductase inhibitor, a squalene synthase inhibitor, a betinicacid-type hypolipidemic drug, an ACAT inhibitor, a lipoxygenaseinhibitor, a cholesterol absorption inhibitor, an ileum sodium ion/bileacid co-transporter inhibitor, an up-regulator of LDL receptor activity,a nicotinic hypolipidemic drug, a bile acid chelate, or a combinationthereof; or wherein the lipid-lowering drug is selected frompravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin,atorvastatin, rosuvastatin, or a combination thereof.
 17. A method ofinhibiting SGLT1, or improving the intestinal environment, or treating adisease, lessening a disease symptom or delaying the progression oronset of a disease in a subject comprising administering to the subjecta therapeutically effective amount of the compound of claim 1, whereinthe disease is diabetes, diabetic complication, insulin resistance,hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity, syndrome X,atherosclerosis, cardiovascular disease, congestive heart failure,hypomagnesemia, hyponatremia, renal failure, disorders related to bloodconcentration, constipation, or high blood pressure; wherein, thediabetic complication is diabetic retinopathy, diabetic neuropathy ordiabetic nephropathy; the hyperlipidemia is hypertriglyceridemia.
 18. Amethod of inhibiting SGLT1, or improving the intestinal environment, orpreventing or treating a disease, lessening a disease symptom ordelaying the progression or onset of a disease in a subject comprisingadministering to the subject a therapeutically effective amount of thepharmaceutical composition of claim 14, wherein the disease is diabetes,diabetic complication, insulin resistance, hyperglycemia,hyperinsulinemia, hyperlipidemia, obesity, syndrome X, atherosclerosis,cardiovascular disease, congestive heart failure, hypomagnesemia,hyponatremia, renal failure, disorders related to blood concentration,constipation, or high blood pressure; wherein, the diabetic complicationis diabetic retinopathy, diabetic neuropathy or diabetic nephropathy;the hyperlipidemia is hypertriglyceridemia.